Methods and compositions for modulating splicing

ABSTRACT

Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, pharmaceutical compositions comprising the same, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2020/016676 filed on Feb. 4, 2020, which claims the benefit ofU.S. Provisional Application No. 62/801,412 filed on Feb. 5, 2019, U.S.Provisional Application No. 62/801,461 filed on Feb. 5, 2019, U.S.Provisional Application No. 62/801,481 filed on Feb. 5, 2019, U.S.Provisional Application No. 62/801,486 filed on Feb. 5, 2019, U.S.Provisional Application No. 62/801,502 filed on Feb. 5, 2019, U.S.Provisional Application No. 62/801,506 filed on Feb. 5, 2019, U.S.Provisional Application No. 62/801,539 filed on Feb. 5, 2019, U.S.Provisional Application No. 62/801,543 filed on Feb. 5, 2019, U.S.Provisional Application No. 62/802,069 filed on Feb. 6, 2019, U.S.Provisional Application No. 62/801,740 filed on Feb. 6, 2019, U.S.Provisional Application No. 62/801,741 filed on Feb. 6, 2019, and U.S.Provisional Application No. 62/801,742 filed on Feb. 6, 2019, thedisclosures of which are hereby incorporated by reference in theirentirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jul. 30, 2021, isnamed 51503-709_306_SL.txt and is 28,946 bytes in size.

BACKGROUND

The majority of protein-coding genes in the human genome are composed ofmultiple exons (coding regions) that are separated by introns(non-coding regions). Gene expression results in a single precursormessenger RNA (pre-mRNA). The intron sequences are subsequently removedfrom the pre-mRNA by a process called splicing, which results in themature messenger RNA (mRNA). By including different combinations ofexons, alternative splicing gives rise to multiple mRNAs encodingdistinct protein isoforms. The spliceosome, an intracellular complex ofmultiple proteins and ribonucleoproteins, catalyzes splicing.

Current therapeutic approaches to direct and control mRNA expressionrequire methods such as gene therapy, genome editing, or a wide range ofoligonucleotide technologies (antisense, RNAi, etc.). Gene therapy andgenome editing act upstream of transcription of mRNA by influencing theDNA code and thereby changing mRNA expression. Oligonucleotides modulatethe action of RNA via canonical base/base hybridization. The appeal ofthis approach is in the design of the basic pharmacophore of anoligonucleotide, which can be defined in a straightforward fashion byknown base pairing to the target sequence subject. Each of thesetherapeutic modalities suffers from substantial technical, clinical, andregulatory challenges. Some limitations of oligonucleotides astherapeutics (e.g., antisense, RNAi) include unfavorablepharmacokinetics, lack of oral bioavailability, and lack ofblood-brain-barrier penetration, with the latter precluding delivery tothe brain or spinal cord after parenteral drug administration for thetreatment of diseases (e.g., neurological diseases, brain cancers). Inaddition, oligonucleotides are not taken up effectively into solidtumors without a complex delivery system such as lipid nanoparticles.Further, most of the oligonucleotides taken up into cells and tissuesremain in non-functional compartments (e.g., endosomes) and does notgain access to the cytosol and/or nucleus where the target is located

Additionally, to anneal to a target, oligonucleotide therapies requireaccess to complementary base pairs of the target. This approach assumesthat pre-mRNA sequences exist as a linear strand of RNA in the cell.However, pre-mRNA is rarely linear; it has complex secondary andtertiary structure. Further, cis-acting elements (e.g., protein bindingelements) and trans-acting factors (e.g., splicing complex components)can create additional two-dimensional and three-dimensional complexity(e.g., by binding to the pre-mRNA). These features can be potency-andefficacy-limiting for oligonucleotide therapies.

SUMMARY

The novel small molecule splicing modulators (SMSMs) described herein donot suffer from the limitations above, nor the structural and sterichindrances that greatly limit oligonucleotide therapies (e.g., byblocking hybridization to pre-mRNA targets). Small molecules have beenessential in uncovering the mechanisms, regulations, and functions ofmany cellular processes, including DNA replication, transcription, andtranslation. While several recent reports have described screens forsmall molecule effectors of splicing, only a small number ofconstitutive or alternative splicing modulators have been identified andmany of the small-molecule inhibitors lack specificity, lackselectivity, lack potency, exhibit toxicity, or are not orallyavailable. Targeting the RNA transcriptome with small-moleculemodulators represents an untapped therapeutic approach to treat avariety of RNA-mediated diseases. Accordingly, there remains a need todevelop small-molecule RNA modulators useful as therapeutic agents.There is need in the art for novel modulators of splicing orsplicing-dependent processes. Provided herein are small moleculesplicing modulators and uses thereof that fulfill this need.

Provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —O— or —S—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from hydrogen and        deuterium;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —O— or —S—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from the group consisting        of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —O— or —S—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are not the same and selected from the group        consisting of hydrogen, deuterium, F, —OR¹, substituted or        unsubstituted C₁-C₄ alkyl, a substituted or unsubstituted C₁-C₄        fluoroalkyl, and substituted or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —O— or —S—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —O— or —S—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, and R²⁰ is independently        selected from the group consisting of hydrogen, deuterium, F,        —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —NR³—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected from        the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from hydrogen and        deuterium;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —NR³—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, —CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from the group consisting        of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —NR³—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, —CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are not the same and selected from the group        consisting of hydrogen, deuterium, F, —OR¹, substituted or        unsubstituted C₁-C₄ alkyl, a substituted or unsubstituted C₁-C₄        fluoroalkyl, and substituted or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —NR³—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, —CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —NR³—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;

R³ is hydrogen, CN, substituted or unsubstituted C₁-C₄ alkyl, —CD₃,substituted or unsubstituted C₁-C₄ haloalkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;

-   -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, and R²⁰ is independently        selected from the group consisting of hydrogen, deuterium, F,        —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;

R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and deuterium,(ii) are the same and selected from the group consisting of F, —OR¹,substituted or unsubstituted C₁-C₄ alkyl, a substituted or unsubstitutedC₁-C₄ fluoroalkyl, and substituted or unsubstituted C₁-C₄ heteroalkyl,or (iii) are not the same and selected from the group consisting ofhydrogen, deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,a substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted orunsubstituted C₁-C₄ heteroalkyl;

a is 0 or 1;

b is 0;

c is 1; and

d is 0 or 1.

Provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is

-   -   Z is N or CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from hydrogen and        deuterium;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is

-   -   Z is N or CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from the group consisting        of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are not the same and selected from the group        consisting of hydrogen, deuterium, F, —OR¹, substituted or        unsubstituted C₁-C₄ alkyl, a substituted or unsubstituted C₁-C₄        fluoroalkyl, and substituted or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;

-   -   Z is N or CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ia):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ib):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ic):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Id):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ie):

In one embodiment, the compound of Formula (I) has the structure ofFormula (If):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ig):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ih):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ii):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ij):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ik):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Il):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Im):

In one embodiment, the compound of Formula (I) has the structure ofFormula (In):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Io):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ip):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Iq):

In one embodiment, the compound of Formula (I) has the structure ofFormula (Ir):

In one aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is

-   -   Z is N or CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, and R²⁰ is independently        selected from the group consisting of hydrogen, deuterium, F,        —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Provided herein is a compound of Formula (II), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   is a single bond or a double bond;    -   X is

and Z is C; or

-   -   X is

and Z is N or CR²;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R², when present, is hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted        C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from hydrogen and        deuterium;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Provided herein is a compound of Formula (II), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   is a single bond or a double bond;    -   X is

and Z is C; or

-   -   X is

and Z is N or CR²;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R², when present, is hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted        C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from the group consisting        of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Provided herein is a compound of Formula (II), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   is a single bond or a double bond;    -   X is

and Z is C; or

-   -   X is

and Z is N or CR²;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R², when present, is hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted        C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are not the same and selected from the group        consisting of hydrogen, deuterium, F, —OR¹, substituted or        unsubstituted C₁-C₄ alkyl, a substituted or unsubstituted C₁-C₄        fluoroalkyl, and substituted or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (II), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;

is a single bond or a double bond;

-   -   X is

and Z is C; or

-   -   X is

and Z is N or CR²;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R², when present, is hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted        C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIa):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIb):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIc):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIaa):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIbb):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIcc):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IId):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIe):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIf):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIdd):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIee):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIff):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIg):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIh):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIi):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIj):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIgg):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIhh):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIii):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIjj):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIk):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIl):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIm):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIn):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIkk):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIll):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IImm):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IInn):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIo):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIp):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIq):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIr):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIoo):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIpp):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIqq):

In one embodiment, the compound of Formula (II) has the structure ofFormula (IIrr):

In one aspect, described herein is a compound of Formula (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;

is a single bond or a double bond;

-   -   X is

and Z is C; or

-   -   X is

and Z is N or CR²;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R², when present, is hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted        C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, and R²⁰ is independently        selected from the group consisting of hydrogen, deuterium, F,        —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

Also provided herein is a method of modulating splicing comprisingcontacting a compound described herein to cells, wherein the compoundmodulates splicing at a splice site sequence of a pre-mRNA that encodesa mRNA, wherein the mRNA encodes a target protein or a functional RNA.

Provided herein is a method of treating a disease or conditioncomprising administering a compound described herein or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof to a subject in need thereof.

Provided herein is a pharmaceutical composition comprising a compounddescribed herein or a pharmaceutically acceptable salt orpharmaceutically acceptable solvate thereof, and a pharmaceuticallyacceptable excipient or carrier.

Also provided herein is use of a compound described herein or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof in the manufacture of a medicament for the treatment of acondition or disease.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION

Certain specific details of this description are set forth in order toprovide a thorough understanding of various embodiments. However, oneskilled in the art will understand that the present disclosure may bepracticed without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed disclosure.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural referents unless the contentclearly dictates otherwise. It should also be noted that the term “or”is generally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present disclosure, suitable methods andmaterials are described below.

Definitions

The terms “compound(s) of this disclosure”, “compound(s) of the presentdisclosure”, “small molecule steric modulator(s)”, “small moleculesplicing modulator(s)” “steric modulator(s)”, “splicing modulator(s)”,“compound(s) that modify splicing” and “compound(s) modifying splicing”,“SMSM” or “small molecule that binds a target RNA,” are interchangeablyused herein and refer to compounds as disclosed herein andstereoisomers, tautomers, solvates, and salts (e.g., pharmaceuticallyacceptable salts) thereof. The terms “compound(s) of this disclosure”,“compound(s) of the present disclosure”, “small molecule stericmodulator(s)”, “small molecule splicing modulator(s)” “stericmodulator(s)”, “splicing modulator(s)”, “compound(s) that modifysplicing” and “compound(s) modifying splicing”, “SMSM” or “smallmolecule that binds a target RNA,” denote a small molecule compound thatbinds to a cell component (e.g., DNA, RNA, pre-mRNA, protein, RNP,snRNA, carbohydrates, lipids, co-factors, nutrients and/or metabolites)and modulates splicing of a target polynucleotide, e.g., a pre-mRNA. Forexample, an SMSM can bind directly or indirectly to a targetpolynucleotide, e.g., RNA (e.g., a pre-mRNA) with a mutated,non-mutated, bulged and/or aberrant splice site, resulting in modulationof splicing of the target polynucleotide. For example, an SMSM can binddirectly or indirectly to a protein, e.g., a spliceosome protein or aribonuclear protein, resulting in steric modulation of the protein andmodulation of splicing of a target RNA. For example, an SMSM can binddirectly or indirectly to a spliceosome component, e.g., a spliceosomeprotein or snRNA resulting in steric modulation of the spliceosomeprotein or snRNA and modulation of splicing of target polynucleotide.These terms specifically exclude compounds consisting ofoligonucleotides. These terms include small molecule compounds that maybind to one or more secondary or tertiary structure elements of a targetRNA. These sites include RNA triplexes, 3WJs, 4WJs, parallel-Yjunctions, hairpins, bulge loops, pseudoknots, internal loops, and otherhigher-order RNA structural motifs.

The term “RNA” (ribonucleic acid) as used herein, meansnaturally-occurring or synthetic oligoribonucleotides independent ofsource (e.g., the RNA may be produced by a human, animal, plant, virus,or bacterium, or may be synthetic in origin), biological context (e.g.,the RNA may be in the nucleus, circulating in the blood, in vitro, celllysate, or isolated or pure form), or physical form (e.g., the RNA maybe in single-, double-, or triple-stranded form (including RNA-DNAhybrids), may include epigenetic modifications, nativepost-transcriptional modifications, artificial modifications (e.g.,obtained by chemical or in vitro modification), or other modifications,may be bound to, e.g., metal ions, small molecules, proteins such aschaperones, or co-factors, or may be in a denatured, partiallydenatured, or folded state including any native or unnatural secondaryor tertiary structure such as quadruplexes, hairpins, triplexes, threeway junctions (3WJs), four way junctions (4WJs), parallel-Y junctions,hairpins, bulge loops, pseudoknots, and internal loops, etc., and anytransient forms or structures adopted by the RNA). In some embodiments,the RNA is 20, 22, 50, 75, or 100 or more nucleotides in length. In someembodiments, the RNA is 250 or more nucleotides in length. In someembodiments, the RNA is 350, 450, 500, 600, 750, or 1,000, 2,000, 3,000,4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000, or more nucleotidesin length. In some embodiments, the RNA is between 250 and 1,000nucleotides in length. In some embodiments, the RNA is a pre-RNA,pre-miRNA, or pretranscript. In some embodiments, the RNA is anon-coding RNA (ncRNA), messenger RNA (mRNA), micro-RNA (miRNA), aribozyme, riboswitch, lncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA,ceRNA, pseudo-gene, viral RNA, fungal RNA, parasitic RNA, or bacterialRNA.

The term “target polynucleotide” or “target RNA,” as used herein, meansany type of polynucleotide or RNA, respectively, having a splice sitecapable of being modulated by a small molecule compound describedherein. For example, a target polynucleotide” or “target RNA,” may havea secondary or tertiary structure capable of binding a small moleculecompound described herein.

“Steric alteration”, “steric modification” or “steric modulation” hereinrefers to changes in the spatial orientation of chemical moieties withrespect to each other. A person of ordinary skill in the art wouldrecognize steric mechanisms include, but are not limited to, sterichindrance, steric shielding, steric attraction, chain crossing, stericrepulsions, steric inhibition of resonance, and steric inhibition ofprotonation.

Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atomin the structures herein indicates the presence of hydrogen, unlessindicated otherwise.

The definitions described herein apply irrespective of whether the termsin question appear alone or in combination. It is contemplated that thedefinitions described herein can be appended to form chemically-relevantcombinations, such as e.g. “heterocycloalkylaryl”,“haloalkylheteroaryl”, “arylalkylheterocycloalkyl”, or “alkoxyalkyl”.The last member of the combination is the radical which is binding tothe rest of the molecule. The other members of the combination areattached to the binding radical in reversed order in respect of theliteral sequence, e.g. the combination arylalkylheterocycloalkyl refersto a heterocycloalkyl-radical which is substituted by an alkyl which issubstituted by an aryl.

When indicating the number of substituents, the term “one or more”refers to the range from one substituent to the highest possible numberof substitution, i.e. replacement of one hydrogen up to replacement ofall hydrogens by substituents.

The term “optional” or “optionally” denotes that a subsequentlydescribed event or circumstance can but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not.

The term “substituent” denotes an atom or a group of atoms replacing ahydrogen atom on the parent molecule.

The term “substituted” denotes that a specified group bears one or moresubstituents. Where any group can carry multiple substituents and avariety of possible substituents is provided, the substituents areindependently selected and need not to be the same. The term“unsubstituted” means that the specified group bears no substituents.The term “optionally substituted” means that the specified group isunsubstituted or substituted by one or more substituents, independentlychosen from the group of possible substituents. When indicating thenumber of substituents, the term “one or more” means from onesubstituent to the highest possible number of substitution, i.e.replacement of one hydrogen up to replacement of all hydrogens bysubstituents.

The following abbreviations are used throughout the specification:acetic acid (AcOH); ethyl acetate (EtOAc); butyl alcohol (n-BuOH);1,2-dichloroethane (DCE); dichloromethane (CH₂Cl₂, DCM);diisopropylethylamine (Diipea); dimethylformamide (DMF); hydrogenchloride (HCl); methanol (MeOH); methoxymethyl bromide (MOMBr);N-methyl-2-pyrrolidone (NMP); methyl Iodide (MeI); n-propanol (n-PrOH);p-methoxybenzyl (PMB); triethylamine (Et₃N);[1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II);(Pd(dppf)Cl₂); sodium ethane thiolate (EtSNa); sodium acetate (NaOAc);sodium hydride (NaH); sodium hydroxide (NaOH); tetrahydropyran (THP);tetrahydrofuran (THF).

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl.

The term “oxo” refers to the ═O substituent.

The term “thioxo” refers to the ═S substituent.

The term “halo”, “halogen”, and “halide” are used interchangeably hereinand denote fluoro, chloro, bromo, or iodo.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical, having from one to twenty carbon atoms, and which is attachedto the rest of the molecule by a single bond. An alkyl comprising up to10 carbon atoms is referred to as a C₁-C₁₀ alkyl, likewise, for example,an alkyl comprising up to 6 carbon atoms is a C₁-C₆ alkyl. Alkyls (andother moieties defined herein) comprising other numbers of carbon atomsare represented similarly. Alkyl groups include, but are not limited to,C₁-C₁₀ alkyl, C₁-C₉ alkyl, C₁-C₈ alkyl, C₁-C-₇ alkyl, C₁-C₆ alkyl, C₁-C₈alkyl, C₁-C₄ alkyl, C₁-C₃ alkyl, C₁-C₂ alkyl, C₂-C₈ alkyl, C₃-C₈ alkyland C₄-C₈ alkyl. Representative alkyl groups include, but are notlimited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl,i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, thealkyl is methyl or ethyl. In some embodiments, the alkyl is —CH(CH₃)₂ or—C(CH₃)₃. Unless stated otherwise specifically in the specification, analkyl group may be optionally substituted as described below. “Alkylene”or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group.In some embodiments, the alkylene is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—. Insome embodiments, the alkylene is —CH₂—. In some embodiments, thealkylene is —CH₂CH₂—. In some embodiments, the alkylene is —CH₂CH₂CH₂—.

The term “alkoxy” refers to a radical of the formula —OR^(a) where R^(a)is an alkyl radical as defined. Unless stated otherwise specifically inthe specification, an alkoxy group may be optionally substituted asdescribed below. Representative alkoxy groups include, but are notlimited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In someembodiments, the alkoxy is methoxy. In some embodiments, the alkoxy isethoxy.

The term “alkylamino” refers to a radical of the formula —NHR^(a) or—NR^(a)R^(a) where each R^(a) is, independently, an alkyl radical asdefined above. Unless stated otherwise specifically in thespecification, an alkylamino group may be optionally substituted asdescribed below.

The term “alkenyl” refers to a type of alkyl group in which at least onecarbon-carbon double bond is present. In one embodiment, an alkenylgroup has the formula —C(R)═CR^(a) ₂, wherein R^(a) refers to theremaining portions of the alkenyl group, which may be the same ordifferent. In some embodiments, R^(a) is H or an alkyl. In someembodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl(i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.Non-limiting examples of an alkenyl group include —CH═CH₂, —C(CH₃)═CH₂,—CH═CHCH₃, —C(CH₃)═CHCH₃, and —CH₂CH═CH₂.

The term “alkynyl” refers to a type of alkyl group in which at least onecarbon-carbon triple bond is present. In one embodiment, an alkenylgroup has the formula —C≡C—R^(a), wherein R^(a) refers to the remainingportions of the alkynyl group. In some embodiments, R^(a) is H or analkyl. In some embodiments, an alkynyl is selected from ethynyl,propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limitingexamples of an alkynyl group include —C≡CH, —C≡CCH₃ —C≡CCH₂CH₃,—CH₂C≡CH.

The term “aromatic” refers to a planar ring having a delocalized7c-electron system containing 4n+2π electrons, where n is an integer.Aromatics can be optionally substituted. The term “aromatic” includesboth aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups(e.g., pyridinyl, quinolinyl).

The term “aryl” refers to an aromatic ring wherein each of the atomsforming the ring is a carbon atom. Aryl groups can be optionallysubstituted. Examples of aryl groups include, but are not limited tophenyl, and naphthyl. In some embodiments, the aryl is phenyl. Dependingon the structure, an aryl group can be a monoradical or a diradical(i.e., an arylene group). Unless stated otherwise specifically in thespecification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”)is meant to include aryl radicals that are optionally substituted. Insome embodiments, an aryl group is partially reduced to form acycloalkyl group defined herein. In some embodiments, an aryl group isfully reduced to form a cycloalkyl group defined herein.

The term “haloalkyl” denotes an alkyl group wherein at least one of thehydrogen atoms of the alkyl group has been replaced by same or differenthalogen atoms, particularly fluoro atoms. Examples of haloalkyl includemonofluoro-, difluoro-or trifluoro-methyl, -ethyl or -propyl, forexample 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,fluoromethyl, or trifluoromethyl. The term “perhaloalkyl” denotes analkyl group where all hydrogen atoms of the alkyl group have beenreplaced by the same or different halogen atoms.

The term “haloalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by same ordifferent halogen atoms, particularly fluoro atoms. Examples ofhaloalkoxyl include monofluoro-, difluoro-or trifluoro-methoxy, -ethoxyor -propoxy, for example 3,3,3-trifluoropropoxy, 2-fluoroethoxy,2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy. The term“perhaloalkoxy” denotes an alkoxy group where all hydrogen atoms of thealkoxy group have been replaced by the same or different halogen atoms.

The term “bicyclic ring system” denotes two rings which are fused toeach other via a common single or double bond (annelated bicyclic ringsystem), via a sequence of three or more common atoms (bridged bicyclicring system) or via a common single atom (spiro bicyclic ring system).Bicyclic ring systems can be saturated, partially unsaturated,unsaturated or aromatic. Bicyclic ring systems can comprise heteroatomsselected from N, O and S.

The terms “carbocyclic” or “carbocycle” refer to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of thetwo rings of a bicyclic carbocycle is aromatic. In some embodiments,both rings of a bicyclic carbocycle are aromatic. Carbocycle includescycloalkyl and aryl.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. In some embodiments, cycloalkyls are saturatedor partially unsaturated. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls arefused with an aromatic ring (in which case the cycloalkyl is bondedthrough a non-aromatic ring carbon atom). Cycloalkyl groups includegroups having from 3 to 10 ring atoms. Representative cycloalkylsinclude, but are not limited to, cycloalkyls having from three to tencarbon atoms, from three to eight carbon atoms, from three to six carbonatoms, or from three to five carbon atoms. Monocyclic cycloalkylradicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, themonocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. In some embodiments, the monocyclic cycloalkyl iscyclopentenyl or cyclohexenyl. In some embodiments, the monocycliccycloalkyl is cyclopentenyl. Polycyclic radicals include, for example,adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl,decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl,norbornyl and bicycle [1.1.1]pentyl. Unless otherwise statedspecifically in the specification, a cycloalkyl group may be optionallysubstituted.

The term “bridged” refers to any ring structure with two or more ringsthat contains a bridge connecting two bridgehead atoms. The bridgeheadatoms are defined as atoms that are the part of the skeletal frameworkof the molecule and which are bonded to three or more other skeletalatoms. In some embodiments, the bridgehead atoms are C, N, or P. In someembodiments, the bridge is a single atom or a chain of atoms thatconnects two bridgehead atoms. In some embodiments, the bridge is avalence bond that connects two bridgehead atoms. In some embodiments,the bridged ring system is cycloalkyl. In some embodiments, the bridgedring system is heterocycloalkyl.

The term “fused” refers to any ring structure described herein which isfused to an existing ring structure. When the fused ring is aheterocyclyl ring or a heteroaryl ring, any carbon atom on the existingring structure which becomes part of the fused heterocyclyl ring or thefused heteroaryl ring may be replaced with one or more N, S, and Oatoms. The non-limiting examples of fused heterocyclyl or heteroarylring structures include 6-5 fused heterocycle, 6-6 fused heterocycle,5-6 fused heterocycle, 5-5 fused heterocycle, 7-5 fused heterocycle, and5-7 fused heterocycle.

The term “haloalkyl” refers to an alkyl radical, as defined above, thatis substituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically inthe specification, a haloalkyl group may be optionally substituted.

The term “haloalkoxy” refers to an alkoxy radical, as defined above,that is substituted by one or more halo radicals, as defined above,e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy,trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy,3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, and the like. Unless statedotherwise specifically in the specification, a haloalkoxy group may beoptionally substituted.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is aC₁-C₆ fluoroalkyl. In some embodiments, a fluoroalkyl is selected fromtrifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, or —N(aryl)-), sulfur(e.g. —S—, —S(═O)—, or —S(═O)₂—), or combinations thereof. In someembodiments, a heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In some embodiments, a heteroalkyl isattached to the rest of the molecule at a heteroatom of the heteroalkyl.In some embodiments, a heteroalkyl is a C₁-C₆ heteroalkyl.Representative heteroalkyl groups include, but are not limited to—OCH₂OMe, —OCH₂CH₂OH, —OCH₂CH₂OMe, or —OCH₂CH₂OCH₂CH₂NH₂.

The term “heteroalkylene” refers to an alkyl radical as described abovewhere one or more carbon atoms of the alkyl is replaced with a O, N or Satom. “Heteroalkylene” or “heteroalkylene chain” refers to a straight orbranched divalent heteroalkyl chain linking the rest of the molecule toa radical group. Unless stated otherwise specifically in thespecification, the heteroalkyl or heteroalkylene group may be optionallysubstituted as described below. Representative heteroalkylene groupsinclude, but are not limited to —OCH₂CH₂O—, —OCH₂CH₂OCH₂CH₂O—, or—OCH₂CH₂OCH₂CH₂OCH₂CH₂O—.

The term “heterocycloalkyl” refers to a cycloalkyl group that includesat least one heteroatom selected from nitrogen, oxygen, and sulfur.Unless stated otherwise specifically in the specification, theheterocycloalkyl radical may be a monocyclic, or bicyclic ring system,which may include fused (when fused with an aryl or a heteroaryl ring,the heterocycloalkyl is bonded through a non-aromatic ring atom) orbridged ring systems. The nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidized. The nitrogen atom maybe optionally quaternized. The heterocycloalkyl radical is partially orfully saturated. Examples of heterocycloalkyl radicals include, but arenot limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl,tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes allring forms of carbohydrates, including but not limited tomonosaccharides, disaccharides and oligosaccharides. Unless otherwisenoted, heterocycloalkyls have from 2 to 12 carbons in the ring. In someembodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. Insome embodiments, heterocycloalkyls have from 2 to 10 carbons in thering and 1 or 2 N atoms. In some embodiments, heterocycloalkyls havefrom 2 to 10 carbons in the ring and 3 or 4 N atoms. In someembodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms,0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In someembodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms,0-1 O atoms, and 0-1 S atoms in the ring. It is understood that whenreferring to the number of carbon atoms in a heterocycloalkyl, thenumber of carbon atoms in the heterocycloalkyl is not the same as thetotal number of atoms (including the heteroatoms) that make up theheterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).Unless stated otherwise specifically in the specification, aheterocycloalkyl group may be optionally substituted.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) that includes at least one heteroatom selectedfrom nitrogen, oxygen and sulfur, wherein each heterocyclic group hasfrom 3 to 12 atoms in its ring system, and with the proviso that anyring does not contain two adjacent O or S atoms. In some embodiments,heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic orbridged compounds. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include rings having 3 to 12 atoms in its ring systemand aromatic heterocyclic groups include rings having 5 to 12 atoms inits ring system. The heterocyclic groups include benzo-fused ringsystems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl,dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, ₃ h-indolyl, indolin-2-onyl,isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic.

The term “heteroaryl” refers to an aryl group that includes one or morering heteroatoms selected from nitrogen, oxygen and sulfur. Theheteroaryl is monocyclic or bicyclic. Illustrative examples ofmonocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl,pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl,oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran,benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline,isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline,1,8-naphthyridine, and pteridine. Illustrative examples of monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Illustrative examples of bicyclicheteroaryls include indolizine, indole, benzofuran, benzothiophene,indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline,cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, andpteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl,pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In someembodiments, a heteroaryl contains 0-6 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 4-6 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 Patoms, and 0-1 S atoms in the ring. In some embodiments, a heteroarylcontains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In someembodiments, heteroaryl is a C₁-C₉ heteroaryl. In some embodiments,monocyclic heteroaryl is a C₁-C₈ heteroaryl. In some embodiments,monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, a bicyclic heteroaryl is a C₆-C₉ heteroaryl. In someembodiments, a heteroaryl group is partially reduced to form aheterocycloalkyl group defined herein. In some embodiments, a heteroarylgroup is fully reduced to form a heterocycloalkyl group defined herein.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from D, halogen, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some other embodiments, optional substituents are independentlyselected from D, halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂(C₁-C₄ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄ alkyl), —C(═O)N(C₁-C₄alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄ alkyl), —S(═O)₂N(C₁-C₄ alkyl)₂,C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ fluoroalkyl, C₁-C₄ heteroalkyl,C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, —SC₁-C₄ alkyl, —S(═O)C₁-C₄ alkyl, and—S(═O)₂(C₁-C₄ alkyl). In some embodiments, optional substituents areindependently selected from D, halogen, —CN, —NH₂, —OH, —NH(CH₃),—N(CH₃)₂, —NH(cyclopropyl), —CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. Insome embodiments, substituted groups are substituted with one or two ofthe preceding groups. In some embodiments, an optional substituent on analiphatic carbon atom (acyclic or cyclic) includes oxo (═O).

The term “tautomer” refers to a proton shift from one atom of a moleculeto another atom of the same molecule. The compounds presented herein mayexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomericinterconversions include:

The term “about” or “approximately” can mean within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e. , the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviation,per the practice in the art. Alternatively, “about” can mean a range ofup to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value.Alternatively, particularly with respect to biological systems orprocesses, the term can mean within an order of magnitude, within5-fold, or within 2-fold, of a value.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes (p.o.),intraduodenal routes (i.d.), parenteral injection (including intravenous(i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular(i.m.), intravascular or infusion (inf.)), topical (top.) and rectal(p.r.) administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated; for example areduction and/or alleviation of one or more signs, symptoms, or causesof a disease, or any other desired alteration of a biological system.For example, an “effective amount” for therapeutic uses can be an amountof an agent that provides a clinically significant decrease in one ormore disease symptoms. An appropriate “effective” amount may bedetermined using techniques, such as a dose escalation study, inindividual cases.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in amount, potency or duration a desired effect. Forexample, in regard to enhancing splicing of a target, the term“enhancing” can refer to the ability to increase or prolong splicing,either in amount, potency or duration, of a the target.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human. The term “animal” as usedherein comprises human beings and non-human animals. In one embodiment,a “non-human animal” is a mammal, for example a rodent such as rat or amouse. In one embodiment, a non-human animal is a mouse.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

The term “preventing” or “prevention” of a disease state denotes causingthe clinical symptoms of the disease state not to develop in a subjectthat can be exposed to or predisposed to the disease state, but does notyet experience or display symptoms of the disease state.

The terms “pharmaceutical composition” and “pharmaceutical formulation”(or “formulation”) are used interchangeably and denote a mixture orsolution comprising a therapeutically effective amount of an activepharmaceutical ingredient together with one or more pharmaceuticallyacceptable excipients to be administered to a subject, e.g., a human inneed thereof.

The term “pharmaceutical combination” as used herein, means a productthat results from mixing or combining more than one active ingredientand includes both fixed and non-fixed combinations of the activeingredients. The term “fixed combination” means that the activeingredients, e.g., a compound described herein and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g., administration of three or more activeingredients.

The term “pharmaceutically acceptable” denotes an attribute of amaterial which is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic, and neither biologically nor otherwiseundesirable and is acceptable for veterinary as well as humanpharmaceutical use. “Pharmaceutically acceptable” can refer a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The terms “pharmaceutically acceptable excipient”, “pharmaceuticallyacceptable carrier” and “therapeutically inert excipient” can be usedinterchangeably and denote any pharmaceutically acceptable ingredient ina pharmaceutical composition having no therapeutic activity and beingnon-toxic to the subject administered, such as disintegrators, binders,fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants,surfactants, carriers, diluents, excipients, preservatives or lubricantsused in formulating pharmaceutical products

The term “pharmaceutically acceptable salts” denotes salts which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltsinclude both acid and base addition salts. A “pharmaceuticallyacceptable salt” can refer to a formulation of a compound that does notcause significant irritation to an organism to which it is administeredand/or does not abrogate the biological activity and properties of thecompound. In some embodiments, pharmaceutically acceptable salts areobtained by reacting an SMSM compound of any one of Formulas (I)-(IV)with an acid. Pharmaceutically acceptable salts are also obtained byreacting a compound of any one of Formulas (I)-(IV) or with a base toform a salt. The type of pharmaceutical acceptable salts, include, butare not limited to: (1) acid addition salts, formed by reacting the freebase form of the compound with a pharmaceutically acceptable: inorganicacid, such as, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; orwith an organic acid, such as, for example, acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

The term “nucleic acid” as used herein generally refers to one or morenucleobases, nucleosides, or nucleotides, and the term includespolynucleobases, polynucleosides, and polynucleotides.

The term “polynucleotide”, as used herein generally refers to a moleculecomprising two or more linked nucleic acid subunits, e.g., nucleotides,and can be used interchangeably with “oligonucleotide”. For example, apolynucleotide may include one or more nucleotides selected fromadenosine (A), cytosine (C), guanine (G), thymine (T) and uracil (U), orvariants thereof. A nucleotide generally includes a nucleoside and atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more phosphate (PO₃) groups. Anucleotide can include a nucleobase, a five-carbon sugar (either riboseor deoxyribose), and one or more phosphate groups. Ribonucleotidesinclude nucleotides in which the sugar is ribose. Deoxyribonucleotidesinclude nucleotides in which the sugar is deoxyribose. A nucleotide canbe a nucleoside monophosphate, nucleoside diphosphate, nucleosidetriphosphate or a nucleoside polyphosphate. For example, a nucleotidecan be a deoxyribonucleoside polyphosphate, such as adeoxyribonucleoside triphosphate (dNTP), Exemplary dNTPs includedeoxyadenosine triphosphate (dATP), deoxycytidine triphosphate (dCTP),deoxyguanosine triphosphate (dGTP), uridine triphosphate (dUTP) anddeoxythymidine triphosphate (dTTP). dNTPs can also include detectabletags, such as luminescent tags or markers (e.g., fluorophores). Forexample, a nucleotide can be a purine (i.e., A or G, or variant thereof)or a pyrimidine (i.e., C, T or U, or variant thereof). In some examples,a polynucleotide is deoxyribonucleic acid (DNA), ribonucleic acid (RNA),or derivatives or variants thereof. Exemplary polynucleotides include,but are not limited to, short interfering RNA (siRNA), a microRNA(miRNA), a plasmid DNA (pDNA), a short hairpin RNA (shRNA), smallnuclear RNA (snRNA), messenger RNA (mRNA), precursor mRNA (pre-mRNA),antisense RNA (asRNA), and heteronuclear RNA (hnRNA), and encompassesboth the nucleotide sequence and any structural embodiments thereof,such as single-stranded, double-stranded, triple-stranded, helical,hairpin, stem loop, bulge, etc. In some cases, a polynucleotide iscircular. A polynucleotide can have various lengths. For example, apolynucleotide can have a length of at least about 7 bases, 8 bases, 9bases, 10 bases, 20 bases, 30 bases, 40 bases, 50 bases, 100 bases, 200bases, 300 bases, 400 bases, 500 bases, 1 kilobase (kb), 2 kb, 3, kb, 4kb, 5 kb, 10 kb, 50 kb, or more. A polynucleotide can be isolated from acell or a tissue. For example, polynucleotide sequences may compriseisolated and purified DNA/RNA molecules, synthetic DNA/RNA molecules,and/or synthetic DNA/RNA analogs.

Polynucleotides may include one or more nucleotide variants, includingnonstandard nucleotide(s), non-natural nucleotide(s), nucleotideanalog(s) and/or modified nucleotides. Examples of modified nucleotidesinclude, but are not limited to diaminopurine, 5-fluorouracil,5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine,4-acetylcytosine, 5-(carboxyhydroxylmethyl)uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, 5-methyl-2-thiouracil,3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, 2,6-diaminopurine andthe like. In some cases, nucleotides may include modifications in theirphosphate moieties, including modifications to a triphosphate moiety.Non-limiting examples of such modifications include phosphate chains ofgreater length (e.g., a phosphate chain having, 4, 5, 6, 7, 8, 9, 10 ormore phosphate moieties) and modifications with thiol moieties (e.g.,alpha-thiotriphosphate and beta-thiotriphosphates). Nucleic acidmolecules may also be modified at the base moiety (e.g., at one or moreatoms that typically are available to form a hydrogen bond with acomplementary nucleotide and/or at one or more atoms that are nottypically capable of forming a hydrogen bond with a complementarynucleotide), sugar moiety or phosphate backbone. Nucleic acid moleculesmay also contain amine -modified groups, such as amino ally 1-dUTP(aa-dUTP) and aminohexhylacrylamide-dCTP (aha-dCTP) to allow covalentattachment of amine reactive moieties, such as N-hydroxysuccinimideesters (NHS). Alternatives to standard DNA base pairs or RNA base pairsin the oligonucleotides of the present disclosure can provide higherdensity in bits per cubic mm, higher safety (resistant to accidental orpurposeful synthesis of natural toxins), easier discrimination inphoto-programmed polymerases, or lower secondary structure. Suchalternative base pairs compatible with natural and mutant polymerasesfor de novo and/or amplification synthesis are described in Betz K,Malyshev D A, Lavergne T, Welte W, Diederichs K, Dwyer T J, OrdoukhanianP, Romesberg F E, Marx A. Nat. Chem. Biol. 2012 July; 8(7):612-4, whichis herein incorporated by reference for all purposes.

As used herein, the terms “polypeptide”, “protein” and “peptide” areused interchangeably and refer to a polymer of amino acid residueslinked via peptide bonds and which may be composed of two or morepolypeptide chains. The terms “polypeptide”, “protein” and “peptide”refer to a polymer of at least two amino acid monomers joined togetherthrough amide bonds. An amino acid may be the L-optical isomer or theD-optical isomer. More specifically, the terms “polypeptide”, “protein”and “peptide” refer to a molecule composed of two or more amino acids ina specific order; for example, the order as determined by the basesequence of nucleotides in the gene or RNA coding for the protein.Proteins are essential for the structure, function, and regulation ofthe body's cells, tissues, and organs, and each protein has uniquefunctions. Examples are hormones, enzymes, antibodies, and any fragmentsthereof. In some cases, a protein can be a portion of the protein, forexample, a domain, a subdomain, or a motif of the protein. In somecases, a protein can be a variant (or mutation) of the protein, whereinone or more amino acid residues are inserted into, deleted from, and/orsubstituted into the naturally occurring (or at least a known) aminoacid sequence of the protein. A protein or a variant thereof can benaturally occurring or recombinant.

Methods for detection and/or measurement of polypeptides in biologicalmaterial are well known in the art and include, but are not limited to,Western-blotting, flow cytometry, ELISAs, RIAs, and various proteomicstechniques. An exemplary method to measure or detect a polypeptide is animmunoassay, such as an ELISA. This type of protein quantitation can bebased on an antibody capable of capturing a specific antigen, and asecond antibody capable of detecting the captured antigen. Exemplaryassays for detection and/or measurement of polypeptides are described inHarlow, E. and Lane, D. Antibodies: A Laboratory Manual, (1988), ColdSpring Harbor Laboratory Press.

Methods for detection and/or measurement of RNA in biological materialare well known in the art and include, but are not limited to,Northern-blotting, RNA protection assay, RT PCR. Suitable methods aredescribed in Molecular Cloning: A Laboratory Manual (Fourth Edition) ByMichael R. Green, Joseph Sambrook, Peter MacCallum 2012, 2,028 pp, ISBN978-1-936113-42-2.

As used here, a “small molecular weight compound” can be usedinterchangeably with “small molecule” or “small organic molecule”. Smallmolecules refer to compounds other than peptides or oligonucleotides;and typically have molecular weights of less than about 2000 Daltons,e.g., less than about 900 Daltons.

A ribonucleoprotein (RNP) refers to a nucleoprotein that contains RNA. ARNP can be a complex of a ribonucleic acid and an RNA-binding protein.Such a combination can also be referred to as a protein-RNA complex.These complexes can function in a number of biological functions thatinclude, but are not limited to, DNA replication, gene expression,metabolism of RNA, and pre-mRNA splicing. Examples of RNPs include theribosome, the enzyme telomerase, vault ribonucleoproteins, RNase P,heterogeneous nuclear RNPs (hnRNPs) and small nuclear RNPs (snRNPs).

Nascent RNA transcripts from protein-coding genes and mRNA processingintermediates, collectively referred to as pre-mRNA, are generally boundby proteins in the nuclei of eukaryotic cells. From the time nascenttranscripts first emerge from RNA polymerase (e.g., RNA polymerase II)until mature mRNAs are transported into the cytoplasm, the RNA moleculesare associated with an abundant set of splicing complex components(e.g., nuclear proteins and snRNAs). These proteins can be components ofhnRNPs, which can contain heterogeneous nuclear RNA (hnRNA) (e.g.,pre-mRNA and nuclear RNA complexes) of various sizes.

Splicing complex components function in splicing and/or splicingregulation. Splicing complex components can include, but are not limitedto, ribonuclear proteins (RNPs), splicing proteins, small nuclear RNAs(snRNAs), small nuclear ribonucleoproteins (snRNPs), and heterogeneousnuclear ribonucleoproteins (hnRNPs). Splicing complex componentsinclude, but are not limited to, those that may be required forsplicing, such as constitutive splicing, alternative splicing, regulatedsplicing and splicing of specific messages or groups of messages. Agroup of related proteins, the serine arginine rich proteins (SRproteins), can function in constitutive pre-mRNA splicing and may alsoregulate alternative splice-site selection in a concentration-dependentmanner. SR proteins typically have a modular structure that consists ofone or two RNA-recognition motifs (RRMs) and a C-terminal rich inarginine and serine residues (RS domain). Their activity in alternativesplicing may be antagonized by members of the hnRNP A/B family ofproteins. Splicing complex components can also include proteins that areassociated with one or more snRNAs. SR proteins in human include, butare not limited to, SC35, SRp55, SRp40, SRm300, SFRS10, TASR-1, TASR-2,SF2/ASF, 9G8, SRp75, SRp30c, SRp20 and P54/SFRS11. Other splicingcomplex components in human that can be involved in splice siteselection include, but are not limited to, U2 snRNA auxiliary factors(e.g. U2AF65, U2AF35), Urp/U2AF1-RS2, SF1/BBP, CBP80, CBP 20, SF1 andPTB/hnRNP1. hnRNP proteins in humans include, but are not limited to,A1, A2/B1, L, M, K, U, F, H, G, R, I and C1/C2. Human genes encodinghnRNPs include HNRNPA0, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3,HNRNPA2B1, HNRNPAB, HNRNPB1, HNRNPC, HNRNPCL1, HNRNPD, HNRPDL, HNRNPF,HNRNPH1, HNRNPH2, HNRNPH3, HNRNPK, HNRNPL, HNRPLL, HNRNPM, HNRNPR, HNRNPU, HNRNP UL1, HNRNP UL2, HNRNP UL3, and FMR1. Splicing complexcomponents may be stably or transiently associated with a snRNP or witha transcript.

The term “intron” refers to both the DNA sequence within a gene and thecorresponding sequence in the unprocessed RNA transcript. As part of theRNA processing pathway, introns can be removed by RNA splicing eithershortly after or concurrent with transcription. Introns are found in thegenes of most organisms and many viruses. They can be located in a widerange of genes, including those that generate proteins, ribosomal RNA(rRNA), and transfer RNA (tRNA).

An “exon” can be any part of a gene that encodes a part of the finalmature RNA produced by that gene after introns have been removed by RNAsplicing. The term “exon” refers to both the DNA sequence within a geneand to the corresponding sequence in RNA transcripts.

A “spliceosome” can be assembled from snRNAs and protein complexes. Thespliceosome can remove introns from a transcribed pre-mRNA.

“Medium effective dose” (ED₅₀) is the dose at which 50% of a populationexpresses a specified response. “Medium lethal dose” (LD₅₀) is the doseat which 50% of a population dies. “Medium toxic dose” (TD₅₀) is thedose at which 50% of a population expresses a specified toxic effect.One particularly useful pharmacological indicator is the “therapeuticindex” which is traditionally defined as the ratio of LD₅₀ to ED₅₀ orthe ratio of TD₅₀ to ED₅₀. Therapeutic index provides a simple anduseful indicator of the benefit versus adverse effect of a drug. Thosedrugs which have a high therapeutic index have a large therapeuticwindow, i.e., the drugs may be administered over a wider range ofeffective doses without incurring significant adverse events.Conversely, drugs having a small therapeutic index have a smalltherapeutic window (small range of effective doses without incurringsignificant adverse events).

The term “AUC” as used herein refers to an abbreviation for “area underthe curve” in a graph of the concentration of a therapeutic agent overtime in a certain part or tissue, such as blood or plasma, of a subjectto whom the therapeutic agent has been administered.

Small Molecule Splicing Modulators (SMSMs)

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asagents for use in treating, preventing, or ameliorating a disease orcondition associated with a target RNA. The present invention providesthe unexpected discovery that certain small chemical molecules canmodify splicing events in pre-mRNA molecules, herein referred to assmall molecule splicing modulators (SMSMs). These SMSMs can modulatespecific splicing events in specific pre-mRNA molecules. These SMSMs canoperate by a variety of mechanisms to modify splicing events. Forexample, the SMSMs of this invention can: 1) interfere with theformation and/or function and/or other properties of splicing complexes,spliceosomes, and/or their components such as hnRNPs, snRNPs,SR-proteins and other splicing factors or elements, resulting in theprevention or induction of a splicing event in a pre-mRNA molecule. Asanother example; 2) prevent and/or modify post-transcriptionalregulation (e.g., splicing) of gene products, such as hnRNPs, snRNPs,SR-proteins and other splicing factors, which can subsequently beinvolved in the formation and/or function of a spliceosome or splicingcomplex component; 3) prevent and/or modify phosphorylation,glycosylation and/or other modifications of gene products including, butnot limited to, hnRNPs, snRNPs, SR-proteins and other splicing factors,which can subsequently be involved in the formation and/or function of aspliceosome or splicing complex component; 4) bind to and/or otherwiseaffect specific pre-mRNA so that a specific splicing event is preventedor induced, e.g., via a mechanism that does not involve base pairingwith RNA in a sequence-specific manner. The small molecules of thisinvention are different from and are not related to antisense orantigene oligonucleotides.

Described herein are compounds modifying splicing of gene products foruse in the treatment, prevention and/or delay of progression of diseasesor conditions (e.g., cancer). Described herein are compounds modifyingsplicing of gene products wherein the compounds induce atranscriptionally inactive variant or transcript of a gene product.Described herein are compounds modifying splicing of gene productswherein the compounds repress a transcriptionally active variant ortranscript of a gene product.

In some embodiments, a compound of Formula (I)-(IV) is made from racemicstarting materials (and/or intermediate) and separated into theindividual enantiomers by chiral chromatography as an intermediate orfinal product. Unless otherwise stated, it is understood that theabsolute configuration of the separated intermediates and finalcompounds is not determined. In some embodiments, the absolutestereochemistry of the enantiomers as drawn is arbitrarily assigned. Insome embodiments, both enantiomers are synthesized.

In some embodiments, a compound of Formula (I)-(IV) is a singleenantiomer. In some embodiments, a compound of Formula (I)-(IV) is notracemic. In some embodiments, a compound of Formula (I)-(IV) issubstantially free of other isomers. In some embodiments, a compound ofFormula (I)-(IV) is a single isomer substantially free of other isomers.In some embodiments, a compound of Formula (I)-(IV) comprises 25% orless of other isomers. In some embodiments, the compound of Formula(I)-(IV) comprises 20% or less of other isomers. In some embodiments, acompound of Formula (I)-(IV) comprises 15% or less of other isomers. Insome embodiments, a compound of Formula (I)-(IV) comprises 10% or lessof other isomers. In some embodiments, the compound of Formula (I)-(IV)comprises 5% or less of other isomers. In some embodiments, the compoundof Formula (I)-(IV) comprises 1% or less of other isomers.

In some embodiments, a compound of Formula (I)-(IV) has a stereochemicalpurity of at least 75%. In some embodiments, a compound of Formula(I)-(IV) has a stereochemical purity of at least 80%. In someembodiments, a compound of Formula (I)-(IV) has a stereochemical purityof at least 85%. In some embodiments, a compound of Formula (I)-(IV) hasa stereochemical purity of at least 90%. In some embodiments, a compoundof Formula (I)-(IV) has a stereochemical purity of at least 95%. In someembodiments, a compound of Formula (I)-(IV) has a stereochemical purityof at least 96%. In some embodiments, a compound of Formula (I)-(IV) hasa stereochemical purity of at least 97%. In some embodiments, a compoundof Formula (I)-(IV) has a stereochemical purity of at least 98%. In someembodiments, a compound of Formula (I)-(IV) has a stereochemical purityof at least 98%.

In some embodiments, an asymmetric carbon atom of a compound of Formula(I)-(IV) is present in enantiomerically enriched form. In certainembodiments, the asymmetric carbon atom of the compound of Formula(I)-(IV) has at least 50% enantiomeric excess, at least 60% enantiomericexcess, at least 70% enantiomeric excess, at least 80% enantiomericexcess, at least 90% enantiomeric excess, at least 95% enantiomericexcess, or at least 99% enantiomeric excess in the (S)- or(R)-configuration.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —O— or —S—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷ is independently selected from        the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —O— or —S—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from hydrogen and        deuterium;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are both hydrogen. In some embodiments, R¹⁵ and R¹⁸are both deuterium.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —O— or —S—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from the group consisting        of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are the same and selected from F, —OR¹, substitutedor unsubstituted C₁-C₃ alkyl, substituted or unsubstituted C₁-C₃fluoroalkyl, and substituted or unsubstituted C₁-C₃ heteroalkyl. In someembodiments, R¹⁵ and R¹⁸ are the same and selected from F, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂NHCH₃,—CH₂N(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₂F,—CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are the same andselected from F, —CH₃, —CH₂OH, —OCH₂CN, —OH, —OCH₃, —OCH₂CN, —OCF₃,—CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are the sameand selected from F, —CH₃, —OCH₃, —OCF₃, —CH₂F, —CHF₂, and —CF₃. In someembodiments, R¹⁵ and R¹⁸ are the same and selected from F, —CH₃, and—OCH₃. In some embodiments, R¹⁵ and R¹⁸ are F. In some embodiments, R¹⁵and R¹⁸ are —CH₃. In some embodiments, R¹⁵ and R¹⁸ are —OCH₃.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —O— or —S—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are not the same and selected from the group        consisting of hydrogen, deuterium, F, —OR¹, substituted or        unsubstituted C₁-C₄ alkyl, a substituted or unsubstituted C₁-C₄        fluoroalkyl, and substituted or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are not the same and selected from hydrogen,deuterium, F, —OR¹, substituted or unsubstituted C₁-C₃ alkyl,substituted or unsubstituted C₁-C₃ fluoroalkyl, and substituted orunsubstituted C₁-C₃ heteroalkyl. In some embodiments, R¹⁵ and R¹⁸ arenot the same and selected from hydrogen, deuterium, F, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂NHCH₃, —CH₂N(CH₃)₂, —OH,—OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₂F, —CHF₂, and —CF₃. Insome embodiments, R¹⁵ and R¹⁸ are not the same and selected fromhydrogen, deuterium, F, —CH₃, —CH₂OH, —OCH₂CN, —OH, —OCH₃, —OCH₂CN,—OCF₃, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are notthe same and selected from hydrogen, deuterium, F, —CH₃, —OCH₃, —OCF₃,—CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are not thesame and selected from hydrogen, deuterium, F, —CH₃, and —OCH₃. In someembodiments, R¹⁵ is F and R¹⁸ is hydrogen. In some embodiments, R¹⁵ ishydrogen and R¹⁸ is F. In some embodiments, R¹⁵ is hydrogen and R¹⁸ isCH₃. In some embodiments, R¹⁵ is CH₃ and R¹⁸ is hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is

and Z is N or CR²; or

-   -   X is —O—, —S—, or —NR³—, and Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, —CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is

or

and Z is N or CR²; or

-   -   X is —O—, —S—, or —NR³—, and Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, —CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, and R²⁰ is independently        selected from the group consisting of hydrogen, deuterium, F,        —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —O— or —S—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, and R²⁰ is independently        selected from the group consisting of hydrogen, deuterium, F,        —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, E is —NR—. In some embodiments, E is —O—. In some embodiments,E is S(═O). In some embodiments, E is S(═O) and oxygen atom in S(═O) isin the equatorial position. In some embodiments, E is S(═O) and oxygenatom in S(═O) is in the axial position. In some embodiments, E isS(═O)(═NR^(E)). In some embodiments, E is S(═O)(═NR^(E)) and oxygen atomin S(═O)(═NR^(E)) is in the equatorial position, and nitrogen atom inS(═O)(═NR^(E)) is in the axial position. In some embodiments, E isS(═O)(═NR^(E)), and oxygen atom in S(═O)(═NR^(E)) is in the axialposition, and nitrogen atom in S(═O)(═NR^(E)) is in the equatorialposition.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is not hydrogen. In some embodiments, a carbon atom havingR¹⁶ group is in the (S)-configuration. In some embodiments, a carbonatom having R¹⁶ group is in the (R)-configuration.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁷ is not hydrogen. In some embodiments, a carbon atom havingR¹⁷ group is in the (S)-configuration. In some embodiments, a carbonatom having R¹⁷ group is in the (R)-configuration.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is not hydrogen and R¹⁷ is not hydrogen. In someembodiments, a carbon atom having R¹⁶ group is in the (S)-configurationand a carbon atom having R¹⁷ group is in the (S)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (S)-configurationand a carbon atom having R¹⁷ group is in the (R)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (R)-configurationand a carbon atom having R¹⁷ group is in the (S)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (R)-configurationand a carbon atom having R¹⁷ group is in the (R)-configuration.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ia):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ib):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ic):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Id):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ie):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (If):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ig):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ih):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ii):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ij):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ik):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Il):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Im):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (In):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Io):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ip):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Iq):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ir):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is substituted or unsubstituted aryl. In someembodiments, ring Q is 2-hydroxy-phenyl substituted with 1, 2, or 3substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. In someembodiments, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted aryl, wherein if aryl is substituted then it issubstituted with 1 or 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, and substituted or        unsubstituted C₂-C₇ heterocycloalkyl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted heteroaryl, wherein if heteroaryl is substituted then itis substituted with 1 or 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, and substituted or        unsubstituted C₂-C₇ heterocycloalkyl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is

wherein each R^(Q) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CF₃, —OCH₃,—OCH₂CH₃, —CH₂OCH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂; and ring P issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is substituted or unsubstituted heteroaryl. In someembodiments, ring Q is substituted or unsubstituted 5- or 6-memberedmonocyclic heteroaryl. In some embodiments, ring Q is substituted orunsubstituted 6-membered monocyclic heteroaryl. In some embodiments,ring Q is 6-membered monocyclic heteroaryl selected from:

wherein each R^(Q) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CF₃, —OCH₃,—OCH₂CH₃, —CH₂OCH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂; and ring P issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each R^(Q) is independently selected from hydrogen, —F, —Cl,—CN, —OH, —CH₃, —CF₃, or —OCH₃. In some embodiments, ring P issubstituted or unsubstituted heteroaryl. In some embodiments, ring P isheteroaryl selected from the group consisting of:

wherein,

-   -   each R^(B) is independently selected from hydrogen, deuterium,        halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆        alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆        alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted        or unsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl; and    -   m is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R^(B) is H.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein,

-   -   each R^(B) is independently selected from hydrogen, deuterium,        halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆        alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆        alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted        or unsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl; and    -   m is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 0, 1, 2, 3,or 4. In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 1, 2, 3 or4. In some embodiments, R^(B1) is selected from hydrogen, deuterium,substituted or unsubstituted C₁-C₆ alkyl, —CD₃, substituted orunsubstituted C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, andsubstituted or unsubstituted C₂-C₇ heterocycloalkyl. In someembodiments, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 0, 1, 2, 3,or 4. In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1-3R^(B), wherein each R^(B) is independently selected from hydrogen,deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, deuteriumsubstituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1-3R^(B), wherein each R^(B) is independently selected from hydrogen,deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, deuteriumsubstituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1,2, 3, 4, or 5 R^(B), wherein each R^(B) is independently selected fromhydrogen, deuterium, halogen, hydroxy, cyano, substituted orunsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ alkoxy,deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein R^(B1) is selected from hydrogen, deuterium, substituted orunsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₃₋₇ cycloalkyl, and substituted or unsubstituted C₂-C₇heterocycloalkyl, and wherein each of the ring Q group can be optionallysubstituted with 1, 2, 3, 4 or 5 R^(B), wherein each R^(B) isindependently selected from hydrogen, deuterium, halogen, hydroxy,cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃, substituted orunsubstituted C₁-C₆ fluoroalkyl, substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted orunsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃,substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl,and substituted or unsubstituted heteroaryl. In some embodiments, R^(B1)is selected from hydrogen, deuterium, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃₋₇cycloalkyl, and substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each R^(B) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —CH₃, —CF₃, —OH, or —OCH₃. In some embodiments, each R^(B)is independently —F or —OCH₃. In some embodiments, R^(B1) is selectedfrom hydrogen, deuterium, —CH₃, —CF₃, or —CD₃.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-naphthyl substituted at the 3 position with 0, 1,and 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein

-   -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, W is substituted or unsubstituted C₁-C₃ alkylene. In someembodiments, W is —CH₂—. In some embodiments, W is —CH₂CH₂—. In someembodiments, W is —CH₂CH₂CH₂—. In some embodiments, W is substituted orunsubstituted C₁-C₂ heteroalkylene. In some embodiments, W is —CH₂OCH₂—.In some embodiments, W is —CH₂O—, wherein O is attached to a carbon atomhaving R¹⁸ group. In some embodiments, W is substituted or unsubstitutedC₃-C₈ cycloalkylene or substituted or unsubstituted C₂-C₃ alkenylene. Insome embodiments, W is substituted or unsubstituted C₃-C₈ cycloalkylene.In some embodiments, W is cyclopropylene. In some embodiments, W issubstituted or unsubstituted C₂-C₃ alkenylene. In some embodiments, W is—CH═CH—.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₅cycloalkyl, or substituted or unsubstituted C₂-C₄ heterocycloalkyl. Insome embodiments, R is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —C(OH)(CH₃)₂, —CH₂CN, —CH₂C(═O)OCH₃,—CH₂C(═O)OCH₂CH₃, —CH₂C(═O)NHCH₃, —CH₂C(═O)N(CH₃)₂, —CH₂NH₂, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CH₂F, —CHF₂, —CF₃, cyclopropyl, cyclobutyl, oxetanyl,aziridinyl, or azetidinyl. In some embodiments, R is hydrogen, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CN,—CH₂F, —CHF₂, —CF₃, cyclopropyl, or oxetanyl. In some embodiments, R ishydrogen, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CHF₂, —CF₃,cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, —CH₃,—CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, cyclopropyl, or oxetanyl. In someembodiments, R is hydrogen, —CH₃, —CH₂OH, —CH₂CN, —CHF₂, —CF₃, orcyclopropyl. In some embodiments, R is hydrogen, —CH₃, —CH₂CH₃, —CH₂F,—CHF₂, —CF₃, cyclopropyl, or oxetanyl. In some embodiments, R is —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, or —CF₃. In some embodiments, R is hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹¹ is H, D, or F. In some embodiments, R¹¹ is D. In someembodiments, R¹¹ is H. In some embodiments, R¹¹ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹² is H, D, or F. In some embodiments, R¹² is D. In someembodiments, R¹² is H. In some embodiments, R¹² is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹³ is H, D, or F. In some embodiments, R¹³ is D. In someembodiments, R¹³ is H. In some embodiments, R¹³ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁴ is H, D, or F. In some embodiments, R¹⁴ is D. In someembodiments, R¹⁴ is H. In some embodiments, R¹⁴ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ is H, D, F, CH₂F, CHF₂, CF₃, or CH₃. In some embodiments,R¹⁵ is H or D. In some embodiments, R¹⁵ is F, CH₂F, CHF₂, CF₃, or CH₃.In some embodiments, R¹⁵ is F, CF₃, CHF₂, or CH₂F. In some embodiments,R¹⁵ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is H, D, or F. In some embodiments, R¹⁶ is D. In In someembodiments, R¹⁶ is H. some embodiments, R¹⁶ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁷ is H, D, or F. In some embodiments, R¹⁷ is D. In someembodiments, R¹⁷ is H. In some embodiments, R¹⁷ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁸ is H, D, F, CH₂F, CHF₂, CF₃, or CH₃. In some embodiments,R¹⁸ is H or D. In some embodiments, R¹⁸ is F, CH₂F, CHF₂, CF₃, or CH₃.In some embodiments, R¹⁸ is F, CF₃, CHF₂, or CH₂F. In some embodiments,R¹⁸ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, one or more of R¹¹, R^(12,) and R¹⁶ is independently selectedfrom F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted orunsubstituted C₁-C₄fluoroalkyl, and substituted or unsubstituted C₁-C₄heteroalkyl. In some embodiments, one or more of R¹¹, R¹², and R¹⁶ isindependently selected from F, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH,—OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In some embodiments, one or moreof R¹¹, R¹², and R¹⁶ is independently selected from F, —OH, —OCH₃,—OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹¹,R¹², and R¹⁶ are hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, one or more of R¹⁶ and R¹⁷ is independently selected from F,—OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted orunsubstituted C₁-C₄ fluoroalkyl, and substituted or unsubstitutedC₁-C₄heteroalkyl. In some embodiments, one or more of R¹⁶ and R¹⁷ isindependently selected from F, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH,—OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In some embodiments, one or moreof R¹⁶ and R¹⁷ is independently selected from F, —OH, —OCH₃, —OCF₃,—CH₃, —CH₂OH, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁶ and R¹⁷are hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ isF. In some embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, andR¹⁸ is F. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, and R¹⁸ are F. In some embodiments, at least one of R¹¹, R¹²,R¹³, R¹⁴, R¹⁶, and R¹⁷ is F. In some embodiments, one of R¹¹, R¹², R¹³,R¹⁴, R¹⁶, and R¹⁷ is F. In some embodiments, at least two of R¹¹, R¹²,R¹³, R¹⁴, R¹⁶, and R¹⁷ are F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F, CF₃,CHF₂, and CH₃CH₂F. In some embodiments, at least one of R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ is F or C₁-C₄ fluoroalkyl. In someembodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprisesa fluorine. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprise a fluorine. In some embodiments, atleast one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprises a fluorine. Insome embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprises afluorine. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶,and R¹⁷ comprise a fluorine.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of W, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F, CF₃,CHF₂, and CH₃CH₂F. In some embodiments, one of W, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprises a fluorine. In some embodiments, Wcomprises a fluorine.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R² is hydrogen, —CH₃, or —OCH₃. In some embodiments, R² ishydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, X is —O—. In some embodiments, X is —S—.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R^(A) is hydrogen, F, Cl, —CN, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCF₃, —CH₂F, —CHF₂, or —CF₃. In someembodiments, R^(A) is hydrogen, F, Cl, —CN, —CH₃, —OH, —OCH₃, —OCF₃,—CH₂F, —CHF₂, or —CF₃. In some embodiments, R^(A) is hydrogen, F, Cl,—CN, —CH₃, or —OCH₃. In some embodiments, R^(A) is hydrogen, F, Cl, or—CH₃. In some embodiments, R^(A) is hydrogen.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹¹, R¹², R¹⁹, R²⁰ and R¹⁶ are hydrogen.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁹ is hydrogen. In some embodiments, R¹⁹ is H, F, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH,—CH₂CN, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In someembodiments, R¹⁹ is H, F, —OH, —OCH₃, —OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂,and —CF₃. In some embodiments, R¹⁹ is F or —OCH₃.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R²⁰ is hydrogen. In some embodiments, R²⁰ is H, F, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH,—CH₂CN, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In someembodiments, R²⁰ is H, F, —OH, —OCH₃, —OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂,and —CF₃. In some embodiments, R²⁰ is F or —OCH₃.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁹ is H, D, or F. In some embodiments, R¹⁹ is D. In someembodiments, R¹⁹ is H. In some embodiments, R¹⁹ is F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R²⁰ is H, D, or F. In some embodiments, R²⁰ is D. In someembodiments, R²⁰ is H. In some embodiments, R²⁰ is F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ and R¹⁹ are H. In some embodiments, R¹⁶ and R¹⁹ are D. Insome embodiments, R¹⁶ and R¹⁹ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁹ and R²⁰ are H. In some embodiments, R¹⁹ and R²⁰ are D. Insome embodiments, R¹⁹ and R²⁰ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁷ and R²⁰ are H. In some embodiments, R¹⁷ and R²⁰ are D. Insome embodiments, R¹⁷ and R²⁰ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ is F. In some embodiments, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,R¹⁹, R²⁰, and R¹⁸ is F. In some embodiments, at least two of R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ are F. In some embodiments,at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷ is F. In someembodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷is F. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹,R²⁰, and R¹⁷ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F,CF₃, CHF₂, and CH₃CH₂F. In some embodiments, at least one of R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ is F or C₁-C₄ fluoroalkyl. Insome embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ comprises a fluorine. In some embodiments, at least two of R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ comprise a fluorine. Insome embodiments, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, andR¹⁷ comprises a fluorine. In some embodiments, one of R¹¹, R¹², R¹³,R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷ comprises a fluorine. In some embodiments,at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprise a fluorine.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of W, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F,CF₃, CHF₂, and CH₃CH₂F. In some embodiments, one of W, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ comprises a fluorine. In someembodiments, W comprises a fluorine.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —NR³—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, —CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —NR³—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, —CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from hydrogen and        deuterium;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are both hydrogen. In some embodiments, R¹⁵ and R¹⁸are both deuterium.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —NR³—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, —CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from the group consisting        of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are the same and selected from F, —OR¹, substitutedor unsubstituted C₁-C₃ alkyl, substituted or unsubstituted C₁-C₃fluoroalkyl, and substituted or unsubstituted C₁-C₃ heteroalkyl. In someembodiments, R¹⁵ and R¹⁸ are the same and selected from F, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂NHCH₃,—CH₂N(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₂F,—CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are the same andselected from F, —CH₃, —CH₂OH, —OCH₂CN, —OH, —OCH₃, —OCH₂CN, —OCF₃,—CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are the sameand selected from F, —CH₃, —OCH₃, —OCF₃, —CH₂F, —CHF₂, and —CF₃. In someembodiments, R¹⁵ and R¹⁸ are the same and selected from F, —CH₃, and—OCH₃. In some embodiments, R¹⁵ and R¹⁸ are F. In some embodiments, R¹⁵and R¹⁸ are —CH₃. In some embodiments, R¹⁵ and R¹⁸ are —OCH₃.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —NR³—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, —CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are not the same and selected from the group        consisting of hydrogen, deuterium, F, —OR¹, substituted or        unsubstituted C₁-C₄ alkyl, a substituted or unsubstituted C₁-C₄        fluoroalkyl, and substituted or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are not the same and selected from hydrogen,deuterium, F, —OR¹, substituted or unsubstituted C₁-C₃ alkyl,substituted or unsubstituted C₁-C₃ fluoroalkyl, and substituted orunsubstituted C₁-C₃ heteroalkyl. In some embodiments, R¹⁵ and R¹⁸ arenot the same and selected from hydrogen, deuterium, F, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂NHCH₃, —CH₂N(CH₃)₂, —OH,—OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₂F, —CHF₂, and —CF₃. Insome embodiments, R¹⁵ and R¹⁸ are not the same and selected fromhydrogen, deuterium, F, —CH₃, —CH₂OH, —OCH₂CN, —OH, —OCH₃, —OCH₂CN,—OCF₃, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are notthe same and selected from hydrogen, deuterium, F, —CH₃, —OCH₃, —OCF₃,—CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are not thesame and selected from hydrogen, deuterium, F, —CH₃, and —OCH₃. In someembodiments, R¹⁵ is F and R¹⁸ is hydrogen. In some embodiments, R¹⁵ ishydrogen and R¹⁸ is F. In some embodiments, R¹⁵ is hydrogen and R¹⁸ isCH₃. In some embodiments, R¹⁵ is CH₃ and R¹⁸ is hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, E is —NR—. In some embodiments, E is —O—. In some embodiments,E is S(═O). In some embodiments, E is S(═O) and oxygen atom in S(═O) isin the equatorial position. In some embodiments, E is S(═O) and oxygenatom in S(═O) is in the axial position. In some embodiments, E isS(═O)(═NR^(E)). In some embodiments, E is S(═O)(═NR^(E)) and oxygen atomin S(═O)(═NR^(E)) is in the equatorial position, and nitrogen atom inS(═O)(═NR^(E)) is in the axial position. In some embodiments, E isS(═O)(═NR^(E)), and oxygen atom in S(═O)(═NR^(E)) is in the axialposition, and nitrogen atom in S(═O)(═NR^(E)) is in the equatorialposition.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is not hydrogen. In some embodiments, a carbon atom havingR¹⁶ group is in the (S)-configuration. In some embodiments, a carbonatom having R¹⁶ group is in the (R)-configuration.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁷ is not hydrogen. In some embodiments, a carbon atom havingR¹⁷ group is in the (S)-configuration. In some embodiments, a carbonatom having R¹⁷ group is in the (R)-configuration.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is not hydrogen and R¹⁷ is not hydrogen. In someembodiments, a carbon atom having R¹⁶ group is in the (S)-configurationand a carbon atom having R¹⁷ group is in the (S)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (S)-configurationand a carbon atom having R¹⁷ group is in the (R)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (R)-configurationand a carbon atom having R¹⁷ group is in the (S)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (R)-configurationand a carbon atom having R¹⁷ group is in the (R)-configuration.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ia):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ib):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ic):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Id):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ie):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (If):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ig):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ih):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ii):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ij):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ik):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Il):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Im):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (In):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Io):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ip):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Iq):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) or (III) has the structure ofFormula (Ir):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is substituted or unsubstituted aryl. In someembodiments, ring Q is 2-hydroxy-phenyl substituted with 1, 2, or 3substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. In someembodiments, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted aryl, wherein if aryl is substituted then it issubstituted with 1 or 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, and substituted or        unsubstituted C₂-C₇ heterocycloalkyl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted heteroaryl, wherein if heteroaryl is substituted then itis substituted with 1 or 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, and substituted or        unsubstituted C₂-C₇ heterocycloalkyl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is

wherein each R^(Q) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, CF₃, OCH₃,—OCH₂CH₃, —CH₂OCH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂; and ring P issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is substituted or unsubstituted heteroaryl. In someembodiments, ring Q is substituted or unsubstituted 5- or 6-memberedmonocyclic heteroaryl. In some embodiments, ring Q is substituted orunsubstituted 6-membered monocyclic heteroaryl. In some embodiments,ring Q is 6-membered monocyclic heteroaryl selected from:

wherein each R^(Q) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CF₃, —OCH₃,—OCH₂CH₃, —CH₂OCH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂; and ring P issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each R^(Q) is independently selected from hydrogen, —F, —Cl,—CN, —OH, —CH₃, —CF₃, or —OCH₃. In some embodiments, ring P issubstituted or unsubstituted heteroaryl. In some embodiments, ring P isheteroaryl selected from the group consisting of:

wherein,

-   -   each R^(B) is independently selected from hydrogen, deuterium,        halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆        alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆        alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted        or unsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl; and    -   m is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein,

-   -   each R^(B) is independently selected from hydrogen, deuterium,        halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆        alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆        alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted        or unsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl; and    -   m is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 0, 1, 2, 3,or 4. In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 1, 2, 3 or4. In some embodiments, R^(B1) is selected from hydrogen, deuterium,substituted or unsubstituted C₁-C₆ alkyl, —CD₃, substituted orunsubstituted C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, andsubstituted or unsubstituted C₂-C₇ heterocycloalkyl. In someembodiments, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 0, 1, 2, 3,or 4. In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1-3R^(B), wherein each R^(B) is independently selected from hydrogen,deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, deuteriumsubstituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1-3R^(B), wherein each R^(B) is independently selected from hydrogen,deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, deuteriumsubstituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1,2, 3, 4, or 5 R^(B), wherein each R^(B) is independently selected fromhydrogen, deuterium, halogen, hydroxy, cyano, substituted orunsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ alkoxy,deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein R^(B1) is selected from hydrogen, deuterium, substituted orunsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₃₋₇ cycloalkyl, and substituted or unsubstituted C₂-C₇heterocycloalkyl, and wherein each of the ring Q group can be optionallysubstituted with 1, 2, 3, 4 or 5 R^(B), wherein each R^(B) isindependently selected from hydrogen, deuterium, halogen, hydroxy,cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃, substituted orunsubstituted C₁-C₆ fluoroalkyl, substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted orunsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃,substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl,and substituted or unsubstituted heteroaryl. In some embodiments, R^(B1)is selected from hydrogen, deuterium, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃₋₇cycloalkyl, and substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each R^(B) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —CH₃, —CF₃, —OH, or —OCH₃. In some embodiments, each R^(B)is independently —F or —OCH₃. In some embodiments, R^(B1) is selectedfrom hydrogen, deuterium, —CH₃, —CF₃, or —CD₃.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-naphthyl substituted at the 3 position with 0, 1,and 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

-   -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, W is substituted or unsubstituted C₁-C₃ alkylene. In someembodiments, W is —CH₂—. In some embodiments, W is —CH₂CH₂—. In someembodiments, W is —CH₂CH₂CH₂—. In some embodiments, W is substituted orunsubstituted C₁-C₂ heteroalkylene. In some embodiments, W is —CH₂OCH₂—.In some embodiments, W is —CH₂O—, wherein O is attached to a carbon atomhaving R¹⁸ group. In some embodiments, W is substituted or unsubstitutedC₃-C₈ cycloalkylene or substituted or unsubstituted C₂-C₃ alkenylene. Insome embodiments, W is substituted or unsubstituted C₃-C₈ cycloalkylene.In some embodiments, W is cyclopropylene. In some embodiments, W issubstituted or unsubstituted C₂-C₃ alkenylene. In some embodiments, W is—CH═CH—.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted C₂-C₄ heterocycloalkyl. Insome embodiments, R is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —C(OH)(CH₃)₂, —CH₂CN, —CH₂C(═O)OCH₃,—CH₂C(═O)OCH₂CH₃, —CH₂C(═O)NHCH₃, —CH₂C(═O)N(CH₃)₂, —CH₂NH₂, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CH₂F, —CHF₂, —CF₃, cyclopropyl, cyclobutyl, oxetanyl,aziridinyl, or azetidinyl. In some embodiments, R is hydrogen, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CN,—CH₂F, —CHF₂, —CF₃, cyclopropyl, or oxetanyl. In some embodiments, R ishydrogen, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CF₃,cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, —CH₃,—CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, cyclopropyl, or oxetanyl. In someembodiments, R is hydrogen, —CH₃, —CH₂OH, —CH₂CN, —CHF₂, —CF₃, orcyclopropyl. In some embodiments, R is hydrogen, —CH₃, —CH₂CH₃, —CH₂F,—CHF₂, —CF₃, cyclopropyl, or oxetanyl. In some embodiments, R is —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, or —CF₃. In some embodiments, R is hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹¹ is H, D, or F. In some embodiments, R¹¹ is D. In someembodiments, R¹¹ is H. In some embodiments, R¹¹ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹² is H, D, or F. In some embodiments, R¹² is D. In someembodiments, R¹² is H. In some embodiments, R¹² is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹³ is H, D, or F. In some embodiments, R¹³ is D. In someembodiments, R¹³ is H. In some embodiments, R¹³ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁴ is H, D, or F. In some embodiments, R¹⁴ is D. In someembodiments, R¹⁴ is H. In some embodiments, R¹⁴ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ is H, D, F, CH₂F, CHF₂, CF₃, or CH₃. In some embodiments,R¹⁵ is H or D. In some embodiments, R¹⁵ is F, CH₂F, CHF₂, CF₃, or CH₃.In some embodiments, R¹⁵ is F, CF₃, CHF₂, or CH₂F. In some embodiments,R¹⁵ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is H, D, or F. In some embodiments, R¹⁶ is D. In In someembodiments, R¹⁶ is H. some embodiments, R¹⁶ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁷ is H, D, or F. In some embodiments, R¹⁷ is D. In someembodiments, R¹⁷ is H. In some embodiments, R¹⁷ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁸ is H, D, F, CH₂F, CHF₂, CF₃, or CH₃. In some embodiments,R¹⁸ is H or D. In some embodiments, R¹⁸ is F, CH₂F, CHF₂, CF₃, or CH₃.In some embodiments, R¹⁸ is F, CF₃, CHF₂, or CH₂F. In some embodiments,R¹⁸ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, one or more of R¹¹, R¹², and R¹⁶ is independently selected fromF, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted orunsubstituted C₁-C₄ fluoroalkyl, and substituted or unsubstituted C₁-C₄heteroalkyl. In some embodiments, one or more of R¹¹, R¹², and R¹⁶ isindependently selected from F, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH,—OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In some embodiments, one or moreof R¹¹, R¹², and R¹⁶ is independently selected from F, —OH, —OCH₃,—OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹¹,R¹², and R¹⁶ are hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, one or more of R¹⁶ and R¹⁷ is independently selected from F,—OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted orunsubstituted C₁-C₄ fluoroalkyl, and substituted or unsubstituted C₁-C₄heteroalkyl. In some embodiments, one or more of R¹⁶ and R¹⁷ isindependently selected from F, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH,—OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In some embodiments, one or moreof R¹⁶ and R¹⁷ is independently selected from F, —OH, —OCH₃, —OCF₃,—CH₃, —CH₂OH, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁶ and R¹⁷are hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ isF. In some embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, andR¹⁸ is F. In some embodiments, at least two of R¹¹, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are F. In some embodiments, at least one of R¹¹,R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is F. In some embodiments, one of R¹¹, R¹²,R¹³, R¹⁴, R¹⁶, and R¹⁷ is F. In some embodiments, at least two of R¹¹,R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ are F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F, CF₃,CHF₂, and CH₃CH₂F. In some embodiments, at least one of R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is F or C₁-C₄ fluoroalkyl. In someembodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprisesa fluorine. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprise a fluorine. In some embodiments, atleast one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprises a fluorine. Insome embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprises afluorine. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶,and R¹⁷ comprise a fluorine.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of W, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, and R¹⁸comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F, CF₃,CHF₂, and CH₃CH₂F. In some embodiments, one of W, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprises a fluorine. In some embodiments, Wcomprises a fluorine.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R² is hydrogen, —CH₃, or —OCH₃. In some embodiments, R² ishydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, X is —NR³—.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R³ is hydrogen, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂F, —CHF₂, or—CF₃. In some embodiments, R³ is hydrogen, —CH₃, —CH₂CH₃, —CH(CH₃)₂, or—CF₃. In some embodiments, R³ is hydrogen, —CH₃, or —CH(CH₃)₂. In someembodiments, R³ is hydrogen or —CH₃.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R^(A) is hydrogen, F, Cl, —CN, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCF₃, —CH₂F, —CHF₂, or —CF₃. In someembodiments, R^(A) is hydrogen, F, Cl, —CN, —CH₃, —OH, —OCH₃, —OCF₃,—CH₂F, —CHF₂, or —CF₃. In some embodiments, R^(A) is hydrogen, F, Cl,—CN, —CH₃, or —OCH₃. In some embodiments, R^(A) is hydrogen, F, Cl, or—CH₃. In some embodiments, R^(A) is hydrogen.

In one aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is —NR³—;    -   Z is CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   R³ is hydrogen, —CN, substituted or unsubstituted C₁-C₄ alkyl,        —CD₃, substituted or unsubstituted C₁-C₄ haloalkyl, substituted        or unsubstituted C₁-C₄ heteroalkyl, or —C₁-C₄ alkylene-OR¹;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, and R²⁰ is independently        selected from the group consisting of hydrogen, deuterium, F,        —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹¹, R¹², R¹⁹, R²⁰ and R¹⁶ are hydrogen.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁹ is hydrogen. In some embodiments, R¹⁹ is H, F, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH,—CH₂CN, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In someembodiments, R¹⁹ is H, F, —OH, —OCH₃, —OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂,and —CF₃. In some embodiments, R¹⁹ is F or —OCH₃.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R²⁰ is hydrogen. In some embodiments, R²⁰ is H, F, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH,—CH₂CN, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In someembodiments, R²⁰ is H, F, —OH, —OCH₃, —OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂,and —CF₃. In some embodiments, R²⁰ is F or —OCH₃.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁹ is H, D, or F. In some embodiments, R¹⁹ is D. In someembodiments, R¹⁹ is H. In some embodiments, R¹⁹ is F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R²⁰ is H, D, or F. In some embodiments, R²⁰ is D. In someembodiments, R²⁰ is H. In some embodiments, R²⁰ is F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ and R¹⁹ are H. In some embodiments, R¹⁶ and R¹⁹ are D. Insome embodiments, R¹⁶ and R¹⁹ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁹ and R²⁰ are H. In some embodiments, R¹⁹ and R²⁰ are D. Insome embodiments, R¹⁹ and R²⁰ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁷ and R²⁰ are H. In some embodiments, R¹⁷ and R²⁰ are D. Insome embodiments, R¹⁷ and R²⁰ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ is F. In some embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁹, R²⁰, and R¹⁸ is F. In some embodiments, at least two of R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ are F. In someembodiments, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷is F. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹,R²⁰, and R¹⁷ is F. In some embodiments, at least two of R¹¹, R¹², R¹³,R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F,CF₃, CHF₂, and CH₃CH₂F. In some embodiments, at least one of R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ is F or C₁-C₄ fluoroalkyl. Insome embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ comprises a fluorine. In some embodiments, at least two of R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ comprise a fluorine. Insome embodiments, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, andR¹⁷ comprises a fluorine. In some embodiments, one of R¹¹, R¹², R¹³,R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷ comprises a fluorine. In some embodiments,at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprise a fluorine.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of W, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F,CF₃, CHF₂, and CH₃CH₂F. In some embodiments, one of W, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ comprises a fluorine. In someembodiments, W comprises a fluorine.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is

-   -   Z is N or CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is

-   -   Z is N or CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from hydrogen and        deuterium;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are both hydrogen. In some embodiments, R¹⁵ and R¹⁸are both deuterium.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is

-   -   Z is N or CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from the group consisting        of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are the same and selected from F, —OR¹, substitutedor unsubstituted C₁-C₃ alkyl, substituted or unsubstituted C₁-C₃fluoroalkyl, and substituted or unsubstituted C₁-C₃ heteroalkyl. In someembodiments, R¹⁵ and R¹⁸ are the same and selected from F, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂NHCH₃,—CH₂N(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₂F,—CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are the same andselected from F, —CH₃, —CH₂OH, —OCH₂CN, —OH, —OCH₃, —OCH₂CN, —OCF₃,—CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are the sameand selected from F, —CH₃, —OCH₃, —OCF₃, —CH₂F, —CHF₂, and —CF₃. In someembodiments, R¹⁵ and R¹⁸ are the same and selected from F, —CH₃, and—OCH₃. In some embodiments, R¹⁵ and R¹⁸ are F. In some embodiments, R¹⁵and R¹⁸ are —CH₃. In some embodiments, R¹⁵ and R¹⁸ are —OCH₃.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is

-   -   Z is N or CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are not the same and selected from the group        consisting of hydrogen, deuterium, F, —OR¹, substituted or        unsubstituted C₁-C₄ alkyl, a substituted or unsubstituted C₁-C₄        fluoroalkyl, and substituted or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are not the same and selected from hydrogen,deuterium, F, —OR¹, substituted or unsubstituted C₁-C₃ alkyl,substituted or unsubstituted C₁-C₃ fluoroalkyl, and substituted orunsubstituted C₁-C₃ heteroalkyl. In some embodiments, R¹⁵ and R¹⁸ arenot the same and selected from hydrogen, deuterium, F, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂NHCH₃, —CH₂N(CH₃)₂, —OH,—OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₂F, —CHF₂, and —CF₃. Insome embodiments, R¹⁵ and R¹⁸ are not the same and selected fromhydrogen, deuterium, F, —CH₃, —CH₂OH, —OCH₂CN, —OH, —OCH₃, —OCH₂CN,—OCF₃, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are notthe same and selected from hydrogen, deuterium, F, —CH₃, —OCH₃, —OCF₃,—CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are not thesame and selected from hydrogen, deuterium, F, —CH₃, and —OCH₃. In someembodiments, R¹⁵ is F and R¹⁸ is hydrogen. In some embodiments, R¹⁵ ishydrogen and R¹⁸ is F. In some embodiments, R¹⁵ is hydrogen and R¹⁸ isCH₃. In some embodiments, R¹⁵ is CH₃ and R¹⁸ is hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   X is

-   -   Z is N or CR²;    -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, deuterium, substituted or unsubstituted C₁-C₄        alkyl, —CD₃, or substituted or unsubstituted C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, and R²⁰ is independently        selected from the group consisting of hydrogen, deuterium, F,        —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, E is —NR—. In some embodiments, E is —O—. In some embodiments,E is S(═O). In some embodiments, E is S(═O) and oxygen atom in S(═O) isin the equatorial position. In some embodiments, E is S(═O) and oxygenatom in S(═O) is in the axial position. In some embodiments, E isS(═O)(═NR^(E)). In some embodiments, E is S(═O)(═NR^(E)) and oxygen atomin S(═O)(═NR^(E)) is in the equatorial position, and nitrogen atom inS(═O)(═NR^(E)) is in the axial position.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, E is S(═O)(═NR^(E)), and oxygen atom in S(═O)(═NR^(E)) is inthe axial position, and nitrogen atom in S(═O)(═NR^(E)) is in theequatorial position.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is not hydrogen. In some embodiments, a carbon atom havingR¹⁶ group is in the (S)-configuration. In some embodiments, a carbonatom having R¹⁶ group is in the (R)-configuration.

In some embodiments R¹⁷ is not hydrogen. In some embodiments, a carbonatom having R¹⁷ group is in the (S)-configuration. In some embodiments,a carbon atom having R¹⁷ group is in the (R)-configuration.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is not hydrogen and R¹⁷ is not hydrogen. In someembodiments, a carbon atom having R¹⁶ group is in the (S)-configurationand a carbon atom having R¹⁷ group is in the (S)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (S)-configurationand a carbon atom having R¹⁷ group is in the (R)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (R)-configurationand a carbon atom having R¹⁷ group is in the (S)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (R)-configurationand a carbon atom having R¹⁷ group is in the (R)-configuration.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ia):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ib):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ic):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Id):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ie):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (If):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ig):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ih):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ii):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ij):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ik):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Il):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Im):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (In):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Io):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ip):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Iq):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound of Formula (I) has the structure of Formula (Ir):

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is substituted or unsubstituted aryl. In someembodiments, ring Q is 2-hydroxy-phenyl substituted with 1, 2, or 3substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. In someembodiments, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted aryl, wherein if aryl is substituted then it issubstituted with 1 or 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, and substituted or        unsubstituted C₂-C₇ heterocycloalkyl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted heteroaryl, wherein if heteroaryl is substituted then itis substituted with 1 or 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, and substituted or        unsubstituted C₂-C₇ heterocycloalkyl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is

wherein each R^(Q) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, CF₃, OCH₃,—OCH₂CH₃, —CH₂OCH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂; and ring P issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is substituted or unsubstituted heteroaryl. In someembodiments, ring Q is substituted or unsubstituted 5- or 6-memberedmonocyclic heteroaryl. In some embodiments, ring Q is substituted orunsubstituted 6-membered monocyclic heteroaryl. In some embodiments,ring Q is 6-membered monocyclic heteroaryl selected from:

wherein each R^(Q) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CF₃, —OCH₃,—OCH₂CH₃, —CH₂OCH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂; and ring P issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each RQ is independently selected from hydrogen, —F, —Cl, —CN,—OH, —CH₃, —CF₃, or —OCH₃. In some embodiments, ring P is substituted orunsubstituted heteroaryl. In some embodiments, ring P is heteroarylselected from the group consisting of:

wherein,

-   -   each R^(B) is independently selected from hydrogen, deuterium,        halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆        alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆        alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted        or unsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl; and    -   m is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein,

-   -   each R^(B) is independently selected from hydrogen, deuterium,        halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆        alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆        alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted        or unsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl; and    -   m is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 0, 1, 2, 3,or 4. In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 1, 2, 3 or4. In some embodiments, R^(B1) is selected from hydrogen, deuterium,substituted or unsubstituted C₁-C₆ alkyl, —CD₃, substituted orunsubstituted C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, andsubstituted or unsubstituted C₂-C₇ heterocycloalkyl. In someembodiments, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 0, 1, 2, 3,or 4. In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1-3R^(B), wherein each R^(B) is independently selected from hydrogen,deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, deuteriumsubstituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1-3R^(B), wherein each R^(B) is independently selected from hydrogen,deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, deuteriumsubstituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1,2, 3, 4, or 5 R^(B), wherein each R^(B) is independently selected fromhydrogen, deuterium, halogen, hydroxy, cyano, substituted orunsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ alkoxy,deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein R^(B1) is selected from hydrogen, deuterium, substituted orunsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₃₋₇ cycloalkyl, and substituted or unsubstituted C₂-C₇heterocycloalkyl, and wherein each of the ring Q group can be optionallysubstituted with 1, 2, 3, 4 or 5 R^(B), wherein each R^(B) isindependently selected from hydrogen, deuterium, halogen, hydroxy,cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃, substituted orunsubstituted C₁-C₆ fluoroalkyl, substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted orunsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃,substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl,and substituted or unsubstituted heteroaryl. In some embodiments, R^(B1)is selected from hydrogen, deuterium, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃₋₇cycloalkyl, and substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each R^(B) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —CH₃, —CF₃, —OH, or —OCH₃. In some embodiments, each R^(B)is independently —F or —OCH₃. In some embodiments, R^(B1) is selectedfrom hydrogen, deuterium, —CH₃, —CF₃, or —CD₃.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-naphthyl substituted at the 3 position with 0, 1,and 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

-   -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, W is substituted or unsubstituted C₁-C₃ alkylene. In someembodiments, W is —CH₂—. In some embodiments, W is —CH₂CH₂—. In someembodiments, W is —CH₂CH₂CH₂—. In some embodiments, W is substituted orunsubstituted C₁-C₂ heteroalkylene. In some embodiments, W is —CH₂OCH₂—.In some embodiments, W is —CH₂O—, wherein O is attached to a carbon atomhaving R¹⁸ group. In some embodiments, W is substituted or unsubstitutedC₃-C₈ cycloalkylene or substituted or unsubstituted C₂-C₃ alkenylene. Insome embodiments, W is substituted or unsubstituted C₃-C₈ cycloalkylene.In some embodiments, W is cyclopropylene. In some embodiments, W issubstituted or unsubstituted C₂-C₃ alkenylene. In some embodiments, W is—CH═CH—.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted C₂-C₄ heterocycloalkyl. Insome embodiments, R is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —C(OH)(CH₃)₂, —CH₂CN, —CH₂C(═O)OCH₃,—CH₂C(═O)OCH₂CH₃, —CH₂C(═O)NHCH₃, —CH₂C(═O)N(CH₃)₂, —CH₂NH₂, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CH₂F, —CHF₂, —CF₃, cyclopropyl, cyclobutyl, oxetanyl,aziridinyl, or azetidinyl. In some embodiments, R is hydrogen, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CN,—CH₂F, —CHF₂, —CF₃, cyclopropyl, or oxetanyl. In some embodiments, R ishydrogen, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CF₃,cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, —CH₃,—CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, cyclopropyl, or oxetanyl. In someembodiments, R is hydrogen, —CH₃, —CH₂OH, —CH₂CN, —CHF₂, —CF₃, orcyclopropyl. In some embodiments, R is hydrogen, —CH₃, —CH₂CH₃, —CH₂F,—CHF₂, —CF₃, cyclopropyl, or oxetanyl. In some embodiments, R is —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, or —CF₃. In some embodiments, R is hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹¹ is H, D, or F. In some embodiments, R¹¹ is D. In someembodiments, R¹¹ is H. In some embodiments, R¹¹ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹² is H, D, or F. In some embodiments, R¹² is D. In someembodiments, R¹² is H. In some embodiments, R¹² is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹³ is H, D, or F. In some embodiments, R¹³ is D. In someembodiments, R¹³ is H. In some embodiments, R¹³ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁴ is H, D, or F. In some embodiments, R¹⁴ is D. In someembodiments, R¹⁴ is H. In some embodiments, R¹⁴ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ is H, D, F, CH₂F, CHF₂, CF₃, or CH₃. In some embodiments,R¹⁵ is H or D. In some embodiments, R¹⁵ is F, CH₂F, CHF₂, CF₃, or CH₃.In some embodiments, R¹⁵ is F, CF₃, CHF₂, or CH₂F. In some embodiments,R¹⁵ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is H, D, or F. In some embodiments, R¹⁶ is D. In In someembodiments, R¹⁶ is H. some embodiments, R¹⁶ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁷ is H, D, or F. In some embodiments, R¹⁷ is D. In someembodiments, R¹⁷ is H. In some embodiments, R¹⁷ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁸ is H, D, F, CH₂F, CHF₂, CF₃, or CH₃. In some embodiments,R¹⁸ is H or D. In some embodiments, R¹⁸ is F, CH₂F, CHF₂, CF₃, or CH₃.In some embodiments, R¹⁸ is F, CF₃, CHF₂, or CH₂F. In some embodiments,R¹⁸ is F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, one or more of R¹¹, R¹², and R¹⁶ is independently selected fromF, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted orunsubstituted C₁-C₄ fluoroalkyl, and substituted or unsubstituted C₁-C₄heteroalkyl. In some embodiments, one or more of R¹¹, R¹², and R¹⁶ isindependently selected from F, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH,—OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In some embodiments, one or moreof R¹¹, R¹², and R¹⁶ is independently selected from F, —OH, —OCH₃,—OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹¹,R¹², and R¹⁶ are hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, one or more of R¹⁶ and R¹⁷ is independently selected from F,—OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted orunsubstituted C₁-C₄ fluoroalkyl, and substituted or unsubstitutedC₁-C₄heteroalkyl. In some embodiments, one or more of R¹⁶ and R¹⁷ isindependently selected from F, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH,—OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In some embodiments, one or moreof R¹⁶ and R¹⁷ is independently selected from F, —OH, —OCH₃, —OCF₃,—CH₃, —CH₂OH, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁶ and R¹⁷are hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ isF. In some embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, andR¹⁸ is F. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, and R¹⁸ are F. In some embodiments, at least one of R¹¹, R¹²,R¹³, R¹⁴, R¹⁶, and R¹⁷ is F. In some embodiments, one of R¹¹, R¹², R¹³,R¹⁴, R¹⁶, and R¹⁷ is F. In some embodiments, at least two of R¹¹, R¹²,R¹³, R¹⁴, R¹⁶, and R¹⁷ are F.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F, CF₃,CHF₂, and CH₃CH₂F. In some embodiments, at least one of R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is F or C₁-C₄ fluoroalkyl. In someembodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprisesa fluorine. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprise a fluorine. In some embodiments, atleast one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprises a fluorine. Insome embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprises afluorine. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶,and R¹⁷ comprise a fluorine.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of W, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F, CF₃,CHF₂, and CH₃CH₂F. In some embodiments, one of W, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, and R¹⁸ and R¹⁸ comprises a fluorine. In someembodiments, W comprises a fluorine.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R² is hydrogen, —CH₃, or —OCH₃. In some embodiments, R² ishydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R^(A) is hydrogen, F, Cl, —CN, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCF₃, —CH₂F, —CHF₂, or —CF₃. In someembodiments, R^(A) is hydrogen, F, Cl, —CN, —CH₃, —OH, —OCH₃, —OCF₃,—CH₂F, —CHF₂, or —CF₃. In some embodiments, R^(A) is hydrogen, F, Cl,—CN, —CH₃, or —OCH₃. In some embodiments, R^(A) is hydrogen, F, Cl, or—CH₃. In some embodiments, R^(A) is hydrogen.

In some embodiments of a compound of Formula (I) or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each R⁴ is independently hydrogen, substituted or unsubstitutedC₁-C₄ alkyl, substituted or unsubstituted C₁-C₄ haloalkyl, orsubstituted or unsubstituted C₁-C₄ heteroalkyl. In some embodiments,each R⁴ is independently hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂OH, —CH₂CH₂OH, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂OCH₃, —CH₂F, —CHF₂, or—CF₃. In some embodiments, each R⁴ is independently hydrogen, —CH₃,—CH₂CH₃, —CH₂OH, —CH₂OCH₃, —CH₂F, —CHF₂, or —CF₃. In some embodiments,each R⁴ is hydrogen. In some embodiments, each R⁴ is —CH₃.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹¹, R¹², R¹⁹, R²⁰ and R¹⁶ are hydrogen.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁹ is hydrogen. In some embodiments, R¹⁹ is H, F, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH,—CH₂CN, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In someembodiments, R¹⁹ is H, F, —OH, —OCH₃, —OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂,and —CF₃. In some embodiments, R¹⁹ is F or —OCH₃.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R²⁰ is hydrogen. In some embodiments, R²⁰ is H, F, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH,—CH₂CN, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In someembodiments, R²⁰ is H, F, —OH, —OCH₃, —OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂,and —CF₃. In some embodiments, R²⁰ is F or —OCH₃.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁹ is H, D, or F. In some embodiments, R¹⁹ is D. In someembodiments, R¹⁹ is H. In some embodiments, R¹⁹ is F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R²⁰ is H, D, or F. In some embodiments, R²⁰ is D. In someembodiments, R²⁰ is H. In some embodiments, R²⁰ is F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ and R¹⁹ are H. In some embodiments, R¹⁶ and R¹⁹ are D. Insome embodiments, R¹⁶ and R¹⁹ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁹ and R²⁰ are H. In some embodiments, R¹⁹ and R²⁰ are D. Insome embodiments, R¹⁹ and R²⁰ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁷ and R²⁰ are H. In some embodiments, R¹⁷ and R²⁰ are D. Insome embodiments, R¹⁷ and R²⁰ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ is F. In some embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁹, R²⁰, and R¹⁸ is F. In some embodiments, at least two of R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ are F. In someembodiments at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷is F. In some embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, andR¹⁷ is F. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶,R¹⁹, R²⁰, and R¹⁷ are F.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F,CF₃, CHF₂, and CH₃CH₂F. In some embodiments, at least one of R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ is F or C₁-C₄ fluoroalkyl. Insome embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ comprises a fluorine. In some embodiments, at least two of R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ comprise a fluorine. Insome embodiments, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, andR¹⁷ comprises a fluorine. In some embodiments, one of R¹¹, R¹², R¹³,R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷ comprises a fluorine. In some embodiments,at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprise a fluorine.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of W, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F,CF₃, CHF₂, and CH₃CH₂F. In some embodiments, one of W, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ comprises a fluorine. In someembodiments, W comprises a fluorine.

In one aspect, described herein is a compound of Formula (II), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;

is a single bond or a double bond;

-   -   X is

and Z is C; or

-   -   X is

and Z is N or CR²;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R², when present, is hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted        C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄ heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In one aspect, described herein is a compound of Formula (II), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   is a single bond or a double bond;    -   X is

and Z is C; or

-   -   X is

and Z is N or CR²;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R², when present, is hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted        C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from hydrogen and        deuterium;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are both hydrogen. In some embodiments, R¹⁵ and R¹⁸are both deuterium.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (II), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   is a single bond or a double bond;    -   X is

and Z is C; or

-   -   X is

and Z is N or CR²;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R², when present, is hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted        C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are the same and selected from the group consisting        of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are the same and selected from F, —OR¹, substitutedor unsubstituted C₁-C₃ alkyl, substituted or unsubstituted C₁-C₃fluoroalkyl, and substituted or unsubstituted C₁-C₃ heteroalkyl. In someembodiments, R¹⁵ and R¹⁸ are the same and selected from F, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂NHCH₃,—CH₂N(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₂F,—CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are the same andselected from F, —CH₃, —CH₂OH, —OCH₂CN, —OH, —OCH₃, —OCH₂CN, —OCF₃,—CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁵ and R¹⁸ are the sameand selected from F, —CH₃, —OCH₃, —OCF₃, —CH₂F, —CHF₂, and —CF₃. In someembodiments, R¹⁵ and R¹⁸ are the same and selected from F, —CH₃, and—OCH₃. In some embodiments, R¹⁵ and R¹⁸ are F. In some embodiments, R¹⁵and R¹⁸ are —CH₃. In some embodiments, R¹⁵ and R¹⁸ are —OCH₃.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (II), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   is a single bond or a double bond;    -   X is

and Z is C; or

-   -   X is

and Z is N or CR²;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R², when present, is hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted        C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independently selected        from the group consisting of hydrogen, deuterium, F, —OR¹,        substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ are not the same and selected from the group        consisting of hydrogen, deuterium, F, —OR¹, substituted or        unsubstituted C₁-C₄ alkyl, a substituted or unsubstituted C₁-C₄        fluoroalkyl, and substituted or unsubstituted C₁-C₄ heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ and R¹⁸ are not the same and selected from hydrogen,deuterium, F, —OR¹, substituted or unsubstituted C₁-C₃ alkyl,substituted or unsubstituted C₁-C₃ fluoroalkyl, and substituted orunsubstituted C₁-C₃ heteroalkyl. In some embodiments, R¹⁵ and R¹⁸ arenot the same and selected from hydrogen, deuterium, F, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂NHCH₃, —CH₂N(CH₃)₂, —OH,—OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CN, —CHF₂, and —CF₃. In someembodiments, R¹⁵ and R¹⁸ are not the same and selected from hydrogen,deuterium, F, —CH₃, —CH₂OH, —OCH₂CN, —OH, —OCH₃, —OCH₂CN, —CHF₂, and—CF₃. In some embodiments, R¹⁵ and R¹⁸ are not the same and selectedfrom hydrogen, deuterium, F, —CH₃, —OCH₃, —OCF₃, —CH₂F, —CHF₂, and —CF₃.In some embodiments, R¹⁵ and R¹⁸ are not the same and selected fromhydrogen, deuterium, F, —CH₃, and —OCH₃. In some embodiments, R¹⁵ is Fand R¹⁸ is hydrogen. In some embodiments, R¹⁵ is hydrogen and R¹⁸ is F.In some embodiments, R¹⁵ is hydrogen and R¹⁸ is CH₃. In someembodiments, R¹⁵ is CH₃ and R¹⁸ is hydrogen.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, the compound is:

In one aspect, described herein is a compound of Formula (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof:

wherein,

-   -   E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR^(E))—;    -   R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹, —SR¹, —S(═O)R¹,        —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl, substituted        or unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted        C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄        cycloalkyl, or substituted or unsubstituted C₂-C₃        heterocycloalkyl;    -   R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted C₂-C₃ alkenyl, or substituted or unsubstituted        C₂-C₃ alkynyl;    -   ring Q is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   is a single bond or a double bond;    -   X is

and Z is C; or

-   -   X is

and Z is N or CR²;

-   -   W is substituted or unsubstituted C₁-C₃ alkylene, substituted or        unsubstituted C₂-C₃ alkenylene, substituted or unsubstituted        C₁-C₂ heteroalkylene, substituted or unsubstituted C₃-C₈        cycloalkylene, or substituted or unsubstituted C₂-C₇        heterocycloalkylene;    -   R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,        substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted or        unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted        C₃-C₆ cycloalkyl, or substituted or unsubstituted C₂-C₅        heterocycloalkyl;    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R², when present, is hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted        C₁-C₄ haloalkyl;    -   each R⁴ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄        heteroalkyl;    -   each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, and R²⁰ is independently        selected from the group consisting of hydrogen, deuterium, F,        —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted or        unsubstituted C₁-C₄ fluoroalkyl, and substituted or        unsubstituted C₁-C₄ heteroalkyl;    -   R¹⁵ and R¹⁸ (i) are the same and selected from hydrogen and        deuterium, (ii) are the same and selected from the group        consisting of F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,        a substituted or unsubstituted C₁-C₄ fluoroalkyl, and        substituted or unsubstituted C₁-C₄heteroalkyl, or (iii) are not        the same and selected from the group consisting of hydrogen,        deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a        substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted        or unsubstituted C₁-C₄heteroalkyl;    -   a is 0 or 1;    -   b is 0;    -   c is 1; and    -   d is 0 or 1.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, E is —NR—. In some embodiments, E is —O—. In some embodiments,E is S(═O). In some embodiments, E is S(═O) and oxygen atom in S(═O) isin the equatorial position. In some embodiments, E is S(═O) and oxygenatom in S(═O) is in the axial position. In some embodiments, E isS(═O)(═NR^(E)). In some embodiments, E is S(═O)(═NR^(E)) and oxygen atomin S(═O)(═NR^(E)) is in the equatorial position, and nitrogen atom inS(═O)(═NR^(E)) is in the axial position. In some embodiments, E isS(═O)(═NR^(E)), and oxygen atom in S(═O)(═NR^(E)) is in the axialposition, and nitrogen atom in S(═O)(═NR^(E)) is in the equatorialposition.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is not hydrogen. In some embodiments, a carbon atom havingR¹⁶ group is in the (S)-configuration. In some embodiments, a carbonatom having R¹⁶ group is in the (R)-configuration.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁷ is not hydrogen. In some embodiments, a carbon atom havingR¹⁷ group is in the (S)-configuration. In some embodiments, a carbonatom having R¹⁷ group is in the (R)-configuration.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is not hydrogen and R¹⁷ is not hydrogen. In someembodiments, a carbon atom having R¹⁶ group is in the (S)-configurationand a carbon atom having R¹⁷ group is in the (S)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (S)-configurationand a carbon atom having R¹⁷ group is in the (R)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (R)-configurationand a carbon atom having R¹⁷ group is in the (S)-configuration. In someembodiments, a carbon atom having R¹⁶ group is in the (R)-configurationand a carbon atom having R¹⁷ group is in the (R)-configuration.

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIa):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIb):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIc):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIaa):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIbb):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIcc):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IId):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIe):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIf):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIdd):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIee):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIff):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIg):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIh):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIi):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIj):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIgg):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIhh):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIii):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIjj):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIk):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIl):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIm):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIn):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIkk):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIll):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IImm):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IInn):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIo):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIp):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIq):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIr):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIoo):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIpp):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIqq):

In one embodiment, the compound of Formula (II) or (IV) has thestructure of Formula (IIrr):

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is substituted or unsubstituted aryl. In someembodiments, ring Q is 2-hydroxy-phenyl substituted with 1, 2, or 3substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. In someembodiments, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted aryl, wherein if aryl is substituted then it issubstituted with 1 or 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, and substituted or        unsubstituted C₂-C₇ heterocycloalkyl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-hydroxy-phenyl substituted with substituted orunsubstituted heteroaryl, wherein if heteroaryl is substituted then itis substituted with 1 or 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, —SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, and substituted or        unsubstituted C₂-C₇ heterocycloalkyl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is

wherein each R^(Q) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, CF₃, OCH₃,—OCH₂CH₃, —CH₂OCH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂; and ring P issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl. In some embodiments, ring Q is substituted or unsubstitutedheteroaryl. In some embodiments, ring Q is substituted or unsubstituted5- or 6-membered monocyclic heteroaryl. In some embodiments, ring Q issubstituted or unsubstituted 6-membered monocyclic heteroaryl. In someembodiments, ring Q is 6-membered monocyclic heteroaryl selected from:

wherein each R^(Q) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, CF₃, —OCH₃,—OCH₂CH₃, —CH₂OCH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂; and ring P issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each R^(Q) is independently selected from hydrogen, —F, —Cl,—CN, —OH, —CH₃, —CF₃, or —OCH₃. In some embodiments, ring P issubstituted or unsubstituted heteroaryl. In some embodiments, ring P isheteroaryl selected from the group consisting of:

wherein,

-   -   each R^(B) is independently selected from hydrogen, deuterium,        halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆        alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆        alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted        or unsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl; and    -   m is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein,

-   -   each R^(B) is independently selected from hydrogen, deuterium,        halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆        alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆        alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted        or unsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl;    -   R^(B1) is selected from hydrogen, deuterium, substituted or        unsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted        C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆        heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, and        substituted or unsubstituted C₂-C₇ heterocycloalkyl; and    -   m is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 0, 1, 2, 3,or 4. In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 1, 2, 3 or4. In some embodiments, R^(B1) is selected from hydrogen, deuterium,substituted or unsubstituted C₁-C₆ alkyl, —CD₃, substituted orunsubstituted C₁-C₆ fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, andsubstituted or unsubstituted C₂-C₇ heterocycloalkyl. In someembodiments, m is 1, 2, or 3. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring P is heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; and m is 0, 1, 2, 3,or 4. In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1-3R^(B), wherein each R^(B) is independently selected from hydrogen,deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, deuteriumsubstituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1-3R^(B), wherein each R^(B) is independently selected from hydrogen,deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, deuteriumsubstituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein each of the ring Q group can be optionally substituted with 1,2, 3, 4, or 5 R^(B), wherein each R^(B) is independently selected fromhydrogen, deuterium, halogen, hydroxy, cyano, substituted orunsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ alkoxy,deuterium substituted C₁-C₆ alkoxy, —OCD₃, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein R^(B1) is selected from hydrogen, deuterium, substituted orunsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₃₋₇ cycloalkyl, and substituted or unsubstituted C₂-C₇heterocycloalkyl, and wherein each of the ring Q group can be optionallysubstituted with 1, 2, 3, 4 or 5 R^(B), wherein each R^(B) isindependently selected from hydrogen, deuterium, halogen, hydroxy,cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃, substituted orunsubstituted C₁-C₆ fluoroalkyl, substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted orunsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆ alkoxy, —OCD₃,substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl,and substituted or unsubstituted heteroaryl. In some embodiments, R^(B1)is selected from hydrogen, deuterium, substituted or unsubstituted C₁-C₆alkyl, —CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃₋₇cycloalkyl, and substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each R^(B) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, —CH₃, —CF₃, —OH, or —OCH₃. In some embodiments, each R^(B)is independently —F or —OCH₃. In some embodiments, R^(B1) is selectedfrom hydrogen, deuterium, —CH₃, —CF₃, or —CD₃.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is 2-naphthyl substituted at the 3 position with 0, 1,and 2 substituents independently selected from:

-   -   deuterium, halogen, —OH, —NO₂, —CN, SR¹, —S(═O)R¹, —S(═O)₂R¹,        —N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —C(═O)N(R¹)₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted        or unsubstituted C₃-C₇ cycloalkyl, substituted or unsubstituted        C₂-C₇ heterocycloalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted heteroaryl; wherein    -   each R¹ is independently hydrogen, deuterium, substituted or        unsubstituted C₁-C₄ alkyl, —CD₃, substituted or unsubstituted        C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,        substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or        unsubstituted C₂-C₅ heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, ring Q is selected from the group consisting of:

wherein R^(B1) is selected from hydrogen, deuterium, substituted orunsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₃₋₇ cycloalkyl, and substituted or unsubstituted C₂-C₇heterocycloalkyl.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, W is substituted or unsubstituted C₁-C₃ alkylene. In someembodiments, W is —CH₂—. In some embodiments, W is —CH₂CH₂—. In someembodiments, W is —CH₂CH₂CH₂—. In some embodiments, W is substituted orunsubstituted C₁-C₂ heteroalkylene. In some embodiments, W is —CH₂OCH₂—.In some embodiments, W is —CH₂O—, wherein O is attached to a carbon atomhaving R¹⁸ group. In some embodiments, W is substituted or unsubstitutedC₃-C₈ cycloalkylene or substituted or unsubstituted C₂-C₃ alkenylene. Insome embodiments, W is substituted or unsubstituted C₃-C₈ cycloalkylene.In some embodiments, W is cyclopropylene. In some embodiments, W issubstituted or unsubstituted C₂-C₃ alkenylene. In some embodiments, W is—CH═CH—.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,substituted or unsubstituted C₁-C₄ fluoroalkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted C₂-C₄ heterocycloalkyl. Insome embodiments, R is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —C(OH)(CH₃)₂, —CH₂CN, —CH₂C(═O)OCH₃,—CH₂C(═O)OCH₂CH₃, —CH₂C(═O)NHCH₃, —CH₂C(═O)N(CH₃)₂, —CH₂NH₂, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CH₂F, —CHF₂, —CF₃, cyclopropyl, cyclobutyl, oxetanyl,aziridinyl, or azetidinyl. In some embodiments, R is hydrogen, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CN,—CH₂F, —CHF₂, —CF₃, cyclopropyl, or oxetanyl. In some embodiments, R ishydrogen, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CHF₂, —CF₃,cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, —CH₃,—CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, cyclopropyl, or oxetanyl. In someembodiments, R is hydrogen, —CH₃, —CH₂OH, —CH₂CN, —CHF₂, —CF₃, orcyclopropyl. In some embodiments, R is hydrogen, —CH₃, —CH₂CH₃, —CH₂F,—CHF₂, —CF₃, cyclopropyl, or oxetanyl. In some embodiments, R is —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, or —CF₃. In some embodiments, R is hydrogen.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹¹ is H, D, or F. In some embodiments, R¹¹ is D. In someembodiments, R¹¹ is H. In some embodiments, R¹¹ is F.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹² is H, D, or F. In some embodiments, R¹² is D. In someembodiments, R¹² is H. In some embodiments, R¹² is F.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹³ is H, D, or F. In some embodiments, R¹³ is D. In someembodiments, R¹³ is H. In some embodiments, R¹³ is F.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁴ is H, D, or F. In some embodiments, R¹⁴ is D. In someembodiments, R¹⁴ is H. In some embodiments, R¹⁴ is F.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁵ is H, D, F, CH₂F, CHF₂, CF₃, or CH₃. In some embodiments,R¹⁵ is H or D. In some embodiments, R¹⁵ is F, CH₂F, CHF₂, CF₃, or CH₃.In some embodiments, R¹⁵ is F, CF₃, CHF₂, or CH₂F. In some embodiments,R¹⁵ is F.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁶ is H, D, or F. In some embodiments, R¹⁶ is D. In In someembodiments, R¹⁶ is H. some embodiments, R¹⁶ is F.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁷ is H, D, or F. In some embodiments, R¹⁷ is D. In someembodiments, R¹⁷ is H. In some embodiments, R¹⁷ is F.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R¹⁸ is H, D, F, CH₂F, CHF₂, CF₃, or CH₃. In some embodiments,R¹⁸ is H or D. In some embodiments, R¹⁸ is F, CH₂F, CHF₂, CF₃, or CH₃.In some embodiments, R¹⁸ is F, CF₃, CHF₂, or CH₂F. In some embodiments,R¹⁸ is F.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, one or more of R¹¹, R¹², and R¹⁶ is independently selected fromF, —OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted orunsubstituted C₁-C₄ fluoroalkyl, and substituted or unsubstituted C₁-C₄heteroalkyl. In some embodiments, one or more of R¹¹, R¹², and R¹⁶ isindependently selected from F, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH,—OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In some embodiments, one or moreof R¹¹, R¹², and R¹⁶ is independently selected from F, —OH, —OCH₃,—OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹¹,R¹², and R¹⁶ are hydrogen.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, one or more of R¹⁶ and R¹⁷ is independently selected from F,—OR¹, substituted or unsubstituted C₁-C₄ alkyl, a substituted orunsubstituted C₁-C₄ fluoroalkyl, and substituted or unsubstitutedC₁-C₄heteroalkyl. In some embodiments, one or more of R¹⁶ and R¹⁷ isindependently selected from F, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH,—OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In some embodiments, one or moreof R¹⁶ and R¹⁷ is independently selected from F, —OH, —OCH₃, —OCF₃,—CH₃, —CH₂OH, —CH₂F, —CHF₂, and —CF₃. In some embodiments, R¹⁶ and R¹⁷are hydrogen.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ isF. In some embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, andR¹⁸ is F. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, and R¹⁸ are F. In some embodiments, at least one of R¹¹, R¹²,R¹³, R¹⁴, R¹⁶, and R¹⁷ is F. In some embodiments, one of R¹¹, R¹², R¹³,R¹⁴, R¹⁶, and R¹⁷ is F. In some embodiments, at least two of R¹¹, R¹²,R¹³, R¹⁴, R¹⁶, and R¹⁷ are F.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F, CF₃,CHF₂, and CH₃CH₂F. In some embodiments, at least one of R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is F or C₁-C₄ fluoroalkyl. In someembodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprisesa fluorine. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprise a fluorine. In some embodiments, atleast one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprises a fluorine. Insome embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprises afluorine. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶,and R¹⁷ comprise a fluorine.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, at least one of W, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸comprises a fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F, CF₃,CHF₂, and CH₃CH₂F. In some embodiments, one of W, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, and R¹⁸ comprises a fluorine. In some embodiments, Wcomprises a fluorine.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R², when present, is hydrogen, —CH₃, or —OCH₃. In someembodiments, R², when present, is hydrogen.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R^(A) is hydrogen, F, Cl, —CN, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCF₃, —CH₂F, —CHF₂, or —CF₃. In someembodiments, R^(A) is hydrogen, F, Cl, —CN, —CH₃, —OH, —OCH₃, —OCF₃,—CH₂F, —CHF₂, or —CF₃. In some embodiments, R^(A) is hydrogen, F, Cl,—CN, —CH₃, or —OCH₃. In some embodiments, R^(A) is hydrogen, F, Cl, or—CH₃. In some embodiments, R^(A) is hydrogen.

In some embodiments of a compound of Formula (II) or (IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each R⁴ is independently hydrogen, substituted or unsubstitutedC₁-C₄ alkyl, substituted or unsubstituted C₁-C₄ haloalkyl, orsubstituted or unsubstituted C₁-C₄ heteroalkyl. In some embodiments,each R⁴ is independently hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂OH, —CH₂CH₂OH, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂OCH₃, —CH₂F, —CHF₂, or—CF₃. In some embodiments, each R⁴ is independently hydrogen, —CH₃,—CH₂CH₃, —CH₂OH, —CH₂OCH₃, —CH₂F, —CHF₂, or —CF₃. In some embodiments,each R⁴ is hydrogen. In some embodiments, each R⁴ is —CH₃.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, R¹¹,R¹², R¹⁹, R²⁰ and R¹⁶ are hydrogen.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, R¹⁹ ishydrogen. In some embodiments, R¹⁹ is H, F, —OH, —OCH₃, —OCH₂CH₃,—OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In someembodiments, R¹⁹ is H, F, —OH, —OCH₃, —OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂,and —CF₃. In some embodiments, R¹⁹ is F or —OCH₃.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, R²⁰ ishydrogen. In some embodiments, R²⁰ is H, F, —OH, —OCH₃, —OCH₂CH₃,—OCH₂CH₂OH, —OCH₂CN, —OCF₃, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃. In someembodiments, R²⁰ is H, F, —OH, —OCH₃, —OCF₃, —CH₃, —CH₂OH, —CH₂F, —CHF₂,and —CF₃. In some embodiments, R²⁰ is F or —OCH₃.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, R¹⁹ isH, D, or F. In some embodiments, R¹⁹ is D. In some embodiments, R¹⁹ isH. In some embodiments, R¹⁹ is F.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, R²⁰ isH, D, or F. In some embodiments, R²⁰ is D. In some embodiments, R²⁰ isH. In some embodiments, R²⁰ is F.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, R¹⁶ andR¹⁹ are H. In some embodiments, R¹⁶ and R¹⁹ are D. In some embodiments,R¹⁶ and R¹⁹ are F.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, R¹⁹ andR²⁰ are H. In some embodiments, R¹⁹ and R²⁰ are D. In some embodiments,R¹⁹ and R²⁰ are F.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, R¹⁷ andR²⁰ are H. In some embodiments, R¹⁷ and R²⁰ are D. In some embodiments,R¹⁷ and R²⁰ are F.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, at leastone of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ is F. Insome embodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,and R¹⁸ is F. In some embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ and R are F. In some embodiments atleast one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷ is F. In someembodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷ is F. Insome embodiments, at least two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, andR¹⁷ are F.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, at leastone of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ comprises afluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F, CF₃, CHF₂, andCH₃CH₂F. In some embodiments, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ is F or C₁-C₄ fluoroalkyl. In someembodiments, one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸comprises a fluorine. In some embodiments, at least two of R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ comprise a fluorine. In someembodiments, at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁹, R²⁰, and R¹⁷comprises a fluorine. In some embodiments, one of R¹¹, R¹², R¹³, R¹⁴,R¹⁶, R¹⁹, R²⁰, and R¹⁷ comprises a fluorine. In some embodiments, atleast two of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ comprise a fluorine.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate thereof, at leastone of W, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, and R¹⁸ comprisesa fluorine, e.g., F or C₁-C₄ fluoroalkyl such as CH₂F, CF₃, CHF₂, andCH₃CH₂F. In some embodiments, one of W, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁹, R²⁰, and R¹⁸ comprises a fluorine. In some embodiments, Wcomprises a fluorine.

In some embodiments of a compound of Formula (I)-(IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R^(B) is H.

In some embodiments of a compound of Formula (I)-(IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl, orsubstituted or unsubstituted C₃-C₆ cycloalkyl. In some embodiments,R^(E) is hydrogen. In some embodiments, R^(E) is methyl or ethyl.

In some embodiments of a compound of Formula (I)-(IV), or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof, each R¹ is independently hydrogen, deuterium, substituted orunsubstituted C₁-C₄ alkyl, —CD₃, or substituted or unsubstituted C₁-C₄haloalkyl. In some embodiments, each R¹ is independently hydrogen,deuterium, or C₁-C₄ alkyl. In some embodiments, each R¹ is independentlyhydrogen, deuterium, or methyl.

In some embodiments, provided herein is a compound of Table 1A, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1A Exemplary SMSM compounds SMSM# Structure Name 1A-1

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1A-2

2-(6-(((1R,2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1A-3

2-(6-(((1R,2S,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1A-4

2-(6-(((1S,2S,3R,5R)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1A-5

2-(6-(((1S,2R,3R,5S,6R)-2,6-difluoro- 8-azabicyclo[3.2.1]octan-3-yl-1,5-d2)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1A-6

2-(6-(((1R,2S,3S,5R)-6,6-difluoro-2- methoxy-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1A-7

2-(6-(((1S,2R,3R,5S,6S)-2,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1A-8

2-(6-(((1S,2S,3R,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1A-9

2-(6-(((1R,2S,3S,5S)-2-fluoro-7- methyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1A-10

2-(6-(((1S,2S,3R,5S)-2-fluoro-8- azabicyclo[3.2.1]oct-6-en-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(2- methoxypyridin-4-yl)phenol 1A-11

5-(4-fluoro-1H-pyrazol-1-yl)-2-(6- (((1R,2R,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-yl)oxy)- 1,2,4-triazin-3-yl)phenol 1A-12

6-(6-(((1R,2S,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1A-13

6-(6-(((1R,2S,3S,5R)-6,6-difluoro-2- methoxy-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)isoquinolin- 7-ol 1A-14

6-(6-(((1R,2S,3S,5R)-2-fluoro-8- azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1A-15

5-(6-(((1S,2R,3R,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-2-(1H-imidazol-1- yl)pyridin-4-ol 1A-16

6-(6-(((1S,2R,3R,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1A-17

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)thio)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1A-18

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)thio)-1,2,4-triazin-3-yl)-4-fluoro-5-(1H- imidazol-1-yl)phenol 1A-19

2-(6-(((1R,3R,5R)-6,6-difluoro-8- azabicyclo[3.2.1]octan-3-yl)thio)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1A-20

6-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)thio)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1A-21

6-(6-(((1R,3r,5S)-8- azabicyclo[3.2.1]oct-6-en-3-yl)thio)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1A-22

5-(6-(((1R,3s,5S)-9- azabicyclo[3.3.1]nonan-3-yl)thio)-1,2,4-triazin-3-yl)-2-(1H-imidazol-1- yl)pyridin-4-ol 1A-23

6-(6-(((1R,3s,5S)-9- azabicyclo[3.3.1]nonan-3-yl)thio)-1,2,4-triazin-3-yl)isoquinolin-7-ol Table 1B Exemplary SMSM compoundsSMSM# Structure Name 1B-1

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1B-2

2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1B-3

2-(6-(((1R,2S,3S,5S)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1B-4

2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1B-5

2-(6-(((1S,2R,3R,5S,6R)-2,6-difluoro- 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)- 1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1B-6

2-(6-(((1R,2S,3S,5R)-6,6-difluoro-2- methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)- 1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1B-7

2-(6-(((1S,2R,3R,5S,6S)-2,6-difluoro- 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)- 1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1B-8

2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1B-9

2-(6-(((1R,2S,3S,5S)-2-fluoro-1,5,7-trimethyl-9-azabicyclo[3.3.1]nonan-3- yl)oxy)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1B-10

2-(6-(((1S,2S,3R,5S)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(2- methoxypyridin-4-yl)phenol 1B-11

2-(6-(((1R,2R,3S,5R)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(4- fluoro-1H-pyrazol-1-yl)phenol 1B-12

6-(6-(((1R,2S,3S,5S)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)isoquinolin- 7-ol 1B-13

6-(6-(((1R,2S,3S,5R)-6,6-difluoro-2- methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)- 1,2,4-triazin-3-yl)isoquinolin-7-ol1B-14

6-(6-(((1R,2R,3S,5R)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1B-15

5-(6-(((1S,2R,3R,5R)-2-fluoro-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-2-(1H- imidazol-1-yl)pyridin-4-ol 1B-16

6-(6-(((1S,2R,3R,5R)-2-fluoro-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)isoquinolin- 7-ol 1B-17

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)thio)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1B-18

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)thio)-1,2,4-triazin-3-yl)-4-fluoro-5-(1H- imidazol-1-yl)phenol 1B-19

2-(6-(((1R,3R,5R)-6,6-difluoro-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-yl)thio)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1B-20

6-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)thio)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1B-21

6-(6-(((1R,3r,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]oct-6-en-3-yl)thio)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1B-22

5-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)thio)-1,2,4-triazin-3-yl)-2-(1H-imidazol-1- yl)pyridin-4-ol 1B-23

6-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)thio)-1,2,4-triazin-3-yl)isoquinolin-7-ol

In some embodiments, provided herein is a compound of Table 1B, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

In some embodiments, provided herein is a compound of Table 1C, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1C Exemplary SMSM compounds SMSM# Structure Name 1C-1

5-(1H-imidazol-1-yl)-2-(6- (((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)- 1,2,4-triazin-3-yl)phenol 1C-2

2-(6-(((1S,3S,4R,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1C-3

2-(6-(((1S,3S,4S,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1C-4

2-(6-(((1S,2S,3R,5R)-2-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1C-5

2-(6-(((1S,2R,3R,5S,6R)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-yl-5-d)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1C-6

2-(6-(((1R,3S,4S,5R)-7,7-difluoro-4- methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)- 1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1C-7

2-(6-(((1S,2R,3R,5S,6S)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]octan-3- yl)oxy)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1C-8

2-(6-(((1S,2S,3R,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1C-9

2-(6-(((1S,3S,4S,5R)-4-fluoro-1,7- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1C-10

2-(6-(((1S,2S,3R,5S)-2-fluoro-1- methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(2- methoxypyridin-4-yl)phenol 1C-11

2-(6-(((1R,3S,4R,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(4-fluoro- 1H-pyrazol-1-yl)phenol 1C-12

6-(6-(((1S,3S,4S,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-1,2,4-triazin-3-yl)isoquinolin- 7-ol 1C-13

6-(6-(((1R,3S,4S,5R)-7,7-difluoro-4- methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)- 1,2,4-triazin-3-yl)isoquinolin-7-ol1C-14

6-(6-(((1R,3S,4S,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1C-15

5-(6-(((1S,2R,3R,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-2-(1H- imidazol-1-yl)pyridin-4-ol 1C-16

6-(6-(((1S,2R,3R,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)isoquinolin- 7-ol 1C-17

5-(1H-imidazol-1-yl)-2-(6- (((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)thio)- 1,2,4-triazin-3-yl)phenol 1C-18

4-fluoro-5-(1H-imidazol-1-yl)-2-(6- (((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)thio)- 1,2,4-triazin-3-yl)phenol 1C-19

2-(6-(((1R,3S,5R)-6,6-difluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)thio)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1C-20

6-(6-(((1S,3R,5R)-1-methyl-8- azabicyclo[3.2.1]octan-3-yl)thio)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1C-21

6-(6-(((1R,3R,5S)-1-methyl-8- azabicyclo[3.2.1]oct-6-en-3-yl)thio)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1C-22

2-(1H-imidazol-1-yl)-5-(6- (((1S,3R,5R)-1-methyl-9-azabicyclo[3.3.1]nonan-3-yl)thio)- 1,2,4-triazin-3-yl)pyridin-4-ol 1C-23

6-(6-(((1S,3R,5R)-1-methyl-9- azabicyclo[3.3.1]nonan-3-yl)thio)-1,2,4-triazin-3-yl)isoquinolin-7-ol

In some embodiments, provided herein is a compound of Table 1D, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1D Exemplary SMSM compounds SMSM# Structure Name 1D-1

2-(6-(((1R,3s,5S)-8- azabicyc1o[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1D-2

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-4-fluoro-5-(1H-imidazol-1-yl)phenol 1D-3

2-(6-(((1R,2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1D-4

2-(6-(((1S,2S,3R,5R)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1D-5

2-(6-(((1S,2R,3R,5S,6R)-2,6-difluoro- 8-azabicyclo[3.2.1]octan-3-yl-1,5-d2)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1D-6

2-(6-(((1R,25,3S,5R)-6,6-difluoro-2- methoxy-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1D-7

2-(6-(((1S,2R,3R,5S,6S)-2,6-difluoro- 8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1D-8

2-(6-(((1S,2S,3R,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1D-9

2-(6-(((1R,25,3S,5S)-2-fluoro-7- methyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1D-10

2-(6-(((1S,25,3R,5S)-2-fluoro-8- azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(2-methoxypyridin-4-yl)phenol1D-11

5-(4-fluoro-1H-pyrazol-1-yl)-2-(6- (((1R,2R,3S,5R)-2-fluoro-8-azabicyc1o[3.2.1]oct-6-en-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)phenol 1D-12

6-(6-(((1R,2S,3S,5S)-2-fluoro-8- azabicyc1o[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1D-13

6-(6-(((1R,2S,3S,5R)-6,6-difluoro-2- methoxy-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1D-14

6-(6-(((1R,2S,3S,5R)-2-fluoro-8- azabicyc1o[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1D-15

5-(6-(((1S,2R,3R,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 2-(1H-imidazol-1-yl)pyridin-4-ol1D-16

6-(6-(((1S,2R,3R,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol

In some embodiments, provided herein is a compound of Table 1E, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1E Exemplary SMSM compounds SMSM# Structure Name 1E-1

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1E-2

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyc1o[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-4-fluoro-5-(1H-imidazol-1-yl)phenol 1E-3

2-(6-(((1R,2S,3S,5S)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.l]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1E-4

2-(6-(((1S,2R,3R,5R)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.l]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1E-5

2-(6-(((1S,2S,3R,5S,6R)-2,6-difluoro- 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1E-6

2-(6-(((1R,2R,3S,5R)-6,6-difluoro-2- methoxy-1,5-dimethyl-8-azabicyc1o[3.2.1]octan-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1E-7

2-(6-(((1S,2S,3R,5S,6S)-2,6-difluoro- 1,5-dimethyl-8-azabicyc1o[3.2.1]octan-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1E-8

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-4-fluoro-5-(1H-imidazol-1-yl)phenol 1E-9

2-(6-(((1S,2R,3R,5R)-2-fluoro-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1E-10

2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5,7-trimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1E-11

2-(6-(((1S,2R,3R,5S)-2-fluoro-1,5- dimethyl-8-azabicyc1o[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)-5-(2-methoxypyridin-4-yl)phenol1E-12

2-(6-(((1R,2S,3S,5R)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)-5-(4-fluoro-1H-pyrazol-1-yl)phenol 1E-13

6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1E-14

6-(6-(((1R,2R,3S,5R)-6,6-difluoro-2- methoxy-1,5-dimethyl-8-azabicyc1o[3.2.1]octan-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1E-15

6-(6-(((1R,2R,3S,5R)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1E-16

5-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyc1o[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 2-(1H-imidazol-1-yl)pyridin-4-ol1E-17

5-(6-(((1S,2S,3R,5R)-2-fluoro-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 2-(1H-imidazol-1-yl)pyridin-4-ol1E-18

6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol

In some embodiments, provided herein is a compound of Table 1F, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1F Exemplary SMSM compounds SMSM# Structure Name 1F-1

5-(1H-imidazol-1-yl)-2-(6- (methyl((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)- 1,2,4-triazin-3-yl)phenol 1F-2

4-fluoro-5-(1H-imidazol-1-yl)-2-(6- (methyl((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)- 1,2,4-triazin-3-yl)phenol 1F-3

2-(6-(((1S,3S,4R,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1F-4

2-(6-(((1S,2R,3R,5R)-2-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1F-5

2-(6-(((1S,2S,3R,5S,6R)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-yl-5-d)(methyl)amino)-1,2,4-triazin-3- yl)-5-(1H-imidazol-1-yl)phenol1F-6

2-(6-(((1R,3S,4S,5R)-7,7-difluoro-4- methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1F-7

2-(6-(((1S,2S,3R,5S,6S)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1F-8

2-(6-(((1S,2R,3R,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1F-9

2-(6-(((1S,3S,4S,5R)-4-fluoro-1,7- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(1H-imidazol-1-yl)phenol 1F- 10

2-(6-(((1S,2R,3R,5S)-2-fluoro-1- methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 5-(2-methoxypyridin-4-yl)phenol1F-11

2-(6-(((1R,3S,4R,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(4-fluoro-1H-pyrazol-1-yl)phenol 1F-12

6-(6-(((1S,3S,4S,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1F-13

6-(6-(((1R,2R,3S,5R)-6,6-difluoro-2- methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1F-14

6-(6-(((1R,3S,4S,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1F-15

5-(6-(((1S,2S,3R,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)- 2-(1H-imidazol-1-yl)pyridin-4-ol1F-16

6-(6-(((1S,2S,3R,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-1,2,4-triazin-3- yl)isoquinolin-7-ol

In some embodiments, provided herein is a compound of Table 1G, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1G Exemplary SMSM compounds SMSM# Structure Name 1G-1

2-(6-(1-((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1G-2

2-(6-(1-((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-4-fluoro-5-(1H- imidazol-1-yl)phenol 1G-3

2-(6-(1-((1R,2S,3R,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1G-4

2-(6-(1-((1S,2R,3S,5R)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1G-5

2-(6-(1-((1S,2S,3S,5S,6R)-2,6- difluoro-8-azabicyclo[3.2.1]octan-3-yl-1,5-d2)vinyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1G-6

2-(6-(1-((1R,2R,3R,5R)-6,6-difluoro- 2-methoxy-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1G-7

2-(6-(1-((1S,2S,3S,5S,6S)-2,6- difluoro-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1G-8

2-(6-(1-((1S,2R,3S,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1G-9

2-(6-(1-((1R,2R,3R,5S)-2-fluoro-7- methyl-9-azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1G-10

2-(6-(1-((1S,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)- 1,2,4-triazin-3-yl)-5-(2-methoxypyridin-4-yl)phenol 1G-11

5-(4-fluoro-1H-pyrazol-1-yl)-2-(6-(1- ((1R,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)- 1,2,4-triazin-3-yl)phenol 1G-12

6-(6-(1-((1R,2R,3R,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1G-13

6-(6-(1-((1R,2R,3R,5R)-6,6-difluoro- 2-methoxy-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1G-14

6-(6-(1-((1R,2R,3R,5R)-6,6-difluoro- 2-methoxy-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1G-15

5-(6-(1-((1S,2S,3S,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3-yl)-2-(1H-imidazol-1- yl)pyridin-4-ol 1G-16

6-(6-(1-((1S,2S,3S,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3-yl)isoquinolin-7-ol

In some embodiments, provided herein is a compound of Table 1H, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1H Exemplary SMSM compounds SMSM# Structure Name 1H-1

2-(6-(1-((1R,3s,5S)-,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1H-2

2-(6-(1-((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-4-fluoro-5-(1H- imidazol-1-yl)phenol 1H-3

2-(6-(1-((1R,2S,3R,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1H-4

2-(6-(1-((1S,2R,3S,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1H-5

2-(6-(1-((1S,2S,3S,5S,6R)-2,6- difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3- yl)vinyl)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1H-6

2-(6-(1-((1R,2R,3R,5R)-6,6-difluoro- 2-methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1H-7

2-(6-(1-((1S,2S,3S,5S,6S)-2,6- difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1H-8

2-(6-(1-((1S,2R,3S,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1H-9

2-(6-(1-((1R,2R,3R,5S)-2-fluoro- 1,5,7-trimethyl-9-azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1H-10

2-(6-(1-((1S,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(2- methoxypyridin-4-yl)phenol 1H-11

2-(6-(1-((1R,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(4- fluoro-1H-pyrazol-1-yl)phenol1H-12

6-(6-(1-((1R,2R,3R,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3- yl)vinyl)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1H-13

6-(6-(1-((1R,2R,3R,5R)-6,6-difluoro- 2-methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)- 1,2,4-triazin-3-yl)isoquinolin-7-ol1H-14

6-(6-(1-((1R,2R,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en- 3-yl)vinyl)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1H-15

5-(6-(1-((1S,2S,3S,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3-yl)-2-(1H- imidazol-1-yl)pyridin-4-ol 1H-16

6-(6-(1-((1S,2S,3S,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3- yl)vinyl)-1,2,4-triazin-3-yl)isoquinolin-7-ol

In some embodiments, provided herein is a compound of Table 1J, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1J Exemplary SMSM compounds SMSM# Structure Name 1J-1

5-(1H-imidazol-1-yl)-2-(6-(1- ((1S,3R,5R)-1-methyl-8-azabicyc1o[3.2.1]octan-3-yl)vinyl)- 1,2,4-triazin-3-yl)phenol 1J-2

4-fluoro-5-(1H-imidazol-1-yl)-2-(6- (1-((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)- 1,2,4-triazin-3-yl)phenol 1J-3

2-(6-(1-((1S,3R,4S,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1J-4

2-(6-(1-((1S,2R,3S,5R)-2-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1J-5

2-(6-(1-((1S,2S,3S,5S,6R)-2,6- difluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-yl-5- d)vinyl)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1J-6

2-(6-(1-((1R,3R,4R,5R)-7,7-difluoro- 4-methoxy-l-methyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1J-7

2-(6-(1-((1S,2S,3S,5S,6S)-2,6- difluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1- yl)phenol 1J-8

2-(6-(1-((1S,2R,3S,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1J-9

2-(6-(1-((1S,3R,4R,5R)-4-fluoro-1,7-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H- imidazol-1-yl)phenol 1J-10

2-(6-(1-((1S,3R,4R,5R)-4-fluoro-1,7-dimethyl-9-azabicyclo[3.3.1]nonan-3- yl)vinyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1J-11

2-(6-(1-((1R,3R,4S,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)-1,2,4-triazin-3-yl)-5-(4- fluoro-1H-pyrazol-1-yl)phenol 1J-12

6-(6-(1-((1S,3R,4R,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1J-13

6-(6-(1-((1R,3R,4R,5R)-7,7-difluoro- 4-methoxy-1-methyl-8-azabicyc1o[3.2.1]octan-3-yl)vinyl)- 1,2,4-triazin-3-yl)isoquinolin-7-ol1J-14

6-(6-(1-((1R,3R,4R,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1J-15

5-(6-(1-((1S,2S,3S,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3-yl)-2-(1H- imidazol-1-yl)pyridin-4-ol 1J-16

6-(6-(1-((1S,2S,3S,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-yl)vinyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol

In some embodiments, provided herein is a compound of Table 1K, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1K Exemplary SMSM compounds SMSM# Structure Name 1K-1

2-(6-((Z)-((1R,5S)-8- azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1K-2

2-(6-((E)-((1R,5S)-8- azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1K-3

5-(6-((Z)-((1R,5S)-9- azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-2- (1H-imidazol-1-yl)pyridin-4-ol1K-4

5-(6-((E)-((1R,5S)-9- azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-2- (1H-imidazol-1-yl)pyridin-4-ol1K-5

2-(6-((Z)-((1R,2S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1K-6

2-(6-((E)-((1S,2S,5R)-2-fluoro-8- azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (5-methyl-2H-tetrazol-2-yl)phenol1K-7

2-(6-((E)-((1S,2S,5 S,6R)-2-fluoro-6-methoxy-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- ( 1H-imidazol-1-yl)phenol 1K-8

2-(6-((E)-((1S,2S,5S,6R)-2,6-difluoro-8-azabicyclo[3.2.1]octan-3-ylidene-1,5-d2)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1K-9

2-(6-((Z)-((1R,2R,5R)-6,6-difluoro-2-methoxy-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1K-10

2-(6-((E)-((1S,2S,5S,6S)-2,6-difluoro- 8-azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1K-11

2-(6-((E)-((1S,2R,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1K-12

2-(6-((Z)-((1R,2R,5S,7R)-2-fluoro-7- methyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1K-13

2-(6-((E)-((1S,2R,5S)-2-fluoro-8- azabicyc1o[3.2.1]oct-6-en-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (2-methoxypyridin-4-yl)phenol1K-14

6-(6-((Z)-((1R,2S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1K-15

6-(6-((Z)-((1R,2R,5R)-6,6-difluoro-2-methoxy-8-azabicyclo[3.2.1]octan-3- ylidene)methyl)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1K-16

5-(6-((E)-((1S,2S,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-2- ( 1H-imidazol-1-yl)pyridin-4-ol1K-17

6-(6-((E)-((1S,2S,5R)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol

In some embodiments, provided herein is a compound of Table 1L, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1L Exemplary SMSM compounds SMSM# Structure Name 1L-1

2-(6-((Z)-((1R,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1L-2

2-(6-((E)-((1R,5S)-1,5-dimethyl-8- azabicyclo[3.2.]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1L-3

5-(6-((Z)-((1R,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-2- (1H-imidazol-1-yl)pyridin-4-ol1L-4

5-(6-((E)-((1R,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-2- (1H-imidazol-1-yl)pyridin-4-ol1L-5

2-(6-((Z)-((1R,2S,5S)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1L-6

2-(6-((E)-((1S,2S,5R)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (5-methyl-2H-tetrazol-2-yl)phenol1L-7

2-(6-((E)-((1S,2S,5S,6R)-2-fluoro-6- methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3- ylidene)methyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1L-8

2-(6-((E)-((1S,2S,5S,6R)-2,6-difluoro- 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3- ylidene)methyl-d)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1L-9

2-(6-((Z)-((1R,2R,5R)-6,6-difluoro-2- methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3- ylidene)methyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1L-10

2-(6-((E)-((1S,2S,5S,6S)-2,6-difluoro- 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3- ylidene)methyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1L-11

2-(6-((E)-((1S,2R,5R)-2-fluoro-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1L-12

2-(6-((Z)-((1R,2R,5S,7R)-2-fluoro- 1,5,7-trimethyl-9-azabicyclo[3.3.1]nonan-3- ylidene)methyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1L-13

2-(6-((E)-((1S,2R,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-ylidene)methyl)-1,2,4-triazin-3-yl)- 5-(2-methoxypyridin-4-yl)phenol1L-14

6-(6-((Z)-((1R,2S,5S)-2-fluoro-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1L-15

6-(6-((Z)-((1R,2R,5R)-6,6-difluoro-2- methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3- ylidene)methyl)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1L-16

5-(6-((E)-((1S,2S,5R)-2-fluoro-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-2- (1H-imidazol-1-yl)pyridin-4-ol1L-17

6-(6-((E)-((1S,2S,5R)-2-fluoro-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol

In some embodiments, provided herein is a compound of Table 1M, or apharmaceutically acceptable salt or pharmaceutically acceptable solvatethereof.

TABLE 1M Exemplary SMSM compounds SMSM# Structure Name 1M-1

5-(1H-imidazol-1-yl)-2-(6-((E)- ((1S,5R)-1-methyl-8-azabicyclo[3.2.1]octan-3- ylidene)methyl)-1,2,4-triazin-3- yl)phenol1M-2

5-(1H-imidazol-1-yl)-2-(6-((E)- ((1R,5S)-1-methyl-8-azabicyclo[3.2.1]octan-3- ylidene)methyl)-1,2,4-triazin-3- yl)phenol1M-3

2-(1H-imidazol-1-yl)-5-(6-((E)- ((1S,5R)-1-methyl-9-azabicyclo[3.3.1]nonan-3- ylidene)methyl)-1,2,4-triazin-3-yl)pyridin-4-ol 1M-4

2-(1H-imidazol-1-yl)-5-(6-((E)- ((1R,5S)-1-methyl-9-azabicyclo[3.3.1]nonan-3- ylidene)methyl)-1,2,4-triazin-3-yl)pyridin-4-ol 1M-5

2-(6-((Z)-((1S,4S,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1M-6

2-(6-((E)-((1S,2S,5R)-2-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (5-methyl-2H-tetrazol-2-yl)phenol1M-7

2-(6-((E)-((1S,2S,5S,6R)-2-fluoro-6- methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3- ylidene)methyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1M-8

2-(6-((E)-((1S,2S,5S,6R)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene-5-d)methyl)-1,2,4-triazin-3- yl)-5-(1H-imidazol-1-yl)phenol 1M-9

2-(6-((Z)-((1R,4R,5R)-7,7-difluoro-4- methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3- ylidene)methyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1M-10

2-(6-((E)-((1S,2S,5S,6S)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1M-11

2-(6-((E)-((1S,2R,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (1H-imidazol-1-yl)phenol 1M-12

2-(6-((Z)-((1S,4R,5R,7S)-4-fluoro- 1,7-dimethyl-9-azabicyclo[3.3.1]nonan-3- ylidene)methyl)-1,2,4-triazin-3-yl)-5-(1H-imidazol-1-yl)phenol 1M-13

2-(6-((E)-((1S,2R,5S)-2-fluoro-1- methyl-8-azabicyclo[3.2.1]oct-6-en-3-ylidene)methyl)-1,2,4-triazin-3-yl)-5- (2-methoxypyridin-4-yl)phenol1M-14

6-(6-((Z)-((1S,4S,5R)-4-fluoro-1- methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol 1M-15

6-(6-((Z)-((1R,4R,5R)-7,7-difluoro-4- methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3- ylidene)methyl)-1,2,4-triazin-3-yl)isoquinolin-7-ol 1M-16

5-(6-((E)-((1S,2S,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3-yl)-2- (1H-imidazol-1-yl)pyridin-4-ol1M-17

6-(6-((E)-((1S,2S,5R)-2-fluoro-1- methyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)-1,2,4-triazin-3- yl)isoquinolin-7-ol

In some cases, an SMSM provided herein can be designated by more thanone SMSM # in different parts of the application; for example, the samecompound can appear more than once in Tables 1A-1M, Tables 3-7, in theexamples, and in the schemes.

In some embodiments, an SMSM described herein, possesses one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. The compounds and methods provided hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof. In certainembodiments, compounds described herein are prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds/salts, separating the diastereomers and recovering theoptically pure enantiomers. In some embodiments, resolution ofenantiomers is carried out using covalent diastereomeric derivatives ofthe compounds described herein. In another embodiment, diastereomers areseparated by separation/resolution techniques based upon differences insolubility. In other embodiments, separation of stereoisomers isperformed by chromatography or by the forming diastereomeric salts andseparation by recrystallization, or chromatography, or any combinationthereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In oneaspect, stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Anexample, without limitation, of a prodrug is a compound describedherein, which is administered as an ester (the “prodrug”) to facilitatetransmittal across a cell membrane where water solubility is detrimentalto mobility but which then is metabolically hydrolyzed to the carboxylicacid, the active entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

In one aspect, prodrugs are designed to alter the metabolic stability orthe transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacokinetic, pharmacodynamic processes and drug metabolism in vivo,once a pharmaceutically active compound is known, the design of prodrugsof the compound is possible. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401,Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho,“Recent Advances in Oral Prodrug Discovery”, Annual Reports in MedicinalChemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series).

In some cases, some of the herein-described compounds may be a prodrugfor another derivative or active compound.

In some embodiments, sites on the aromatic ring portion of compoundsdescribed herein are susceptible to various metabolic reactionsTherefore incorporation of appropriate substituents on the aromatic ringstructures will reduce, minimize or eliminate this metabolic pathway. Inspecific embodiments, the appropriate substituent to decrease oreliminate the susceptibility of the aromatic ring to metabolic reactionsis, by way of example only, a halogen, or an alkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, suchas, for example, ²H, ₃ h, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³ ₆ cl. Inone aspect, isotopically-labeled compounds described herein, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. In one aspect, substitution with isotopes such as deuteriumaffords certain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms, particularlysolvates. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and may be formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. In some embodiments,solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein can exist in unsolvated as well as solvated forms. Ingeneral, the solvated forms are considered equivalent to the unsolvatedforms for the purposes of the compounds and methods provided herein.

In some embodiments, an SMSM has a molecular weight of at most about2000 Daltons, 1500 Daltons, 1000 Daltons or 900 Daltons. In someembodiments, an SMSM has a molecular weight of at least 100 Daltons, 200Daltons, 300 Daltons, 400 Daltons or 500 Daltons. In some embodiments,an SMSM does not comprise a phosphodiester linkage.

Methods of Making Compounds

Compounds described herein can be synthesized using standard synthetictechniques or using methods known in the art in combination with methodsdescribed herein. Unless otherwise indicated, conventional methods ofmass spectroscopy, NMR, HPLC, protein chemistry, biochemistry,recombinant DNA techniques and pharmacology can be employed. Compoundscan be prepared using standard organic chemistry techniques such asthose described in, for example, March's Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions forthe synthetic transformations described herein may be employed such asvariation of solvent, reaction temperature, reaction time, as well asdifferent chemical reagents and other reaction conditions. The startingmaterials can be available from commercial sources or can be readilyprepared.

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. A detailed description oftechniques applicable to the creation of protecting groups and theirremoval are described in Greene and Wuts, Protective Groups in OrganicSynthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, andKocienski, Protective Groups, Thieme Verlag, New York, N.Y., 1994, whichare incorporated herein by reference for such disclosure).

SMSMs can be made using known techniques and further chemicallymodified, in some embodiments, to facilitate intranuclear transfer to,e.g., a splicing complex component, a spliceosome or a pre-mRNAmolecule. One of ordinary skill in the art will appreciate the standardmedicinal chemistry approaches for chemical modifications forintranuclear transfer (e.g., reducing charge, optimizing size, and/ormodifying lipophilicity).

Pharmaceutical Compositions

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999),herein incorporated by reference for such disclosure.

A pharmaceutical composition can be a mixture of an SMSM describedherein with one or more other chemical components (i.e. pharmaceuticallyacceptable ingredients), such as carriers, excipients, binders, fillingagents, suspending agents, flavoring agents, sweetening agents,disintegrating agents, dispersing agents, surfactants, lubricants,colorants, diluents, solubilizers, moistening agents, plasticizers,stabilizers, penetration enhancers, wetting agents, anti-foaming agents,antioxidants, preservatives, or one or more combination thereof. Thepharmaceutical composition facilitates administration of the compound toan organism.

The compositions described herein can be administered to the subject ina variety of ways, including parenterally, intravenously, intradermally,intramuscularly, colonically, rectally or intraperitoneally. In someembodiments, the small molecule splicing modulator or a pharmaceuticallyacceptable salt thereof is administered by intraperitoneal injection,intramuscular injection, subcutaneous injection, or intravenousinjection of the subject. In some embodiments, the pharmaceuticalcompositions can be administered parenterally, intravenously,intramuscularly or orally. The oral agents comprising a small moleculesplicing modulator can be in any suitable form for oral administration,such as liquid, tablets, capsules, or the like. The oral formulationscan be further coated or treated to prevent or reduce dissolution instomach. The compositions of the present invention can be administeredto a subject using any suitable methods known in the art. Suitableformulations for use in the present invention and methods of deliveryare generally well known in the art. For example, the small moleculesplicing modulators described herein can be formulated as pharmaceuticalcompositions with a pharmaceutically acceptable diluent, carrier orexcipient. The compositions may contain pharmaceutically acceptableauxiliary substances as required to approximate physiological conditionsincluding pH adjusting and buffering agents, tonicity adjusting agents,wetting agents and the like, such as, for example, sodium acetate,sodium lactate, sodium chloride, potassium chloride, calcium chloride,sorbitan monolaurate, triethanolamine oleate, etc.

Pharmaceutical formulations described herein can be administrable to asubject in a variety of ways by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular, intramedullary injections, intrathecal,direct intraventricular, intraperitoneal, intralymphatic, intranasalinjections), intranasal, buccal, topical or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

In some embodiments, the pharmaceutical formulation is in the form of atablet. In other embodiments, pharmaceutical formulations containing anSMSM described herein are in the form of a capsule. In one aspect,liquid formulation dosage forms for oral administration are in the formof aqueous suspensions or solutions selected from the group including,but not limited to, aqueous oral dispersions, emulsions, solutions,elixirs, gels, and syrups.

For administration by inhalation, an SMSM described herein can beformulated for use as an aerosol, a mist or a powder. For buccal orsublingual administration, the compositions may take the form oftablets, lozenges, or gels formulated in a conventional manner. In someembodiments, an SMSM described herein can be prepared as transdermaldosage forms. In some embodiments, an SMSM described herein can beformulated into a pharmaceutical composition suitable for intramuscular,subcutaneous, or intravenous injection. In some embodiments, an SMSMdescribed herein can be administered topically and can be formulatedinto a variety of topically administrable compositions, such assolutions, suspensions, lotions, gels, pastes, medicated sticks, balms,creams or ointments. In some embodiments, an SMSM described herein canbe formulated in rectal compositions such as enemas, rectal gels, rectalfoams, rectal aerosols, suppositories, jelly suppositories, or retentionenemas.

Splicing

Extensive posttranscriptional processing occurs before eukaryoticpre-mRNA matures and exits from the nucleus to the cytoplasm, includingthe addition of a 7-methylguanosine cap at the 5′ end, the cleavage andaddition of a poly-A tail at the 3′ end as well as the removal ofintervening sequences or introns by the spliceosome. The vast majorityof higher eukaryotic genes contain multiple introns that are spliced outwith high precision and fidelity in order to maintain the reading frameof the exons. Splicing of pre-mRNA can utilize the recognition of shortconsensus sequences at the boundaries and within introns and exons by anarray of small nuclear ribonucleoprotein (snRNP) complexes (e.g., snRNPsU1, U2, U4, U5, U6, U11, U12m U4atc and U6 atc) and a large number ofproteins, including spliceosomal proteins and positively as well asnegatively acting splicing modulators.

Serine-arginine-rich (SR)-domain-containing proteins generally serve topromote constitutive splicing. They can also modulate alternativesplicing by binding to intronic or exonic splicing enhancer (ISE) orESE, respectively) sequences. Other pre-mRNA binding proteins, such ashnRNPs, regulate splicing by binding to intronic or exonic splicingsuppressor (ISS or ESS, respectively) sequences and can also act asgeneral splicing modulators. The SR protein family is a class of atleast 10 proteins that have a characteristic serine/arginine rich domainin addition to an RNA-binding. SR proteins are generally thought toenhance splicing by simultaneously binding to U170K, a core component ofthe UI snRNP, at the 5′ splice site, and the U2AF35 at the 3′ splicesite, thus bridging the two ends of the intron. While this particularfunction of SR proteins seems to be redundant, as any individual SRprotein can commit a pre-mRNA for constitutive splicing, the role of thevarious SR proteins in alternative splicing of specific pre-mRNAs isdistinct due in part to their ability to recognize and bind to uniqueconsensus sequences. Phosphorylation of the RS domain of SR proteins canlead to the regulation of their protein interactions, RNA binding,localization, trafficking, and role in alternative splicing. Severalcellular kinases that phosphorylate SR proteins have been identified,including SR protein Kinase (SRPKs), Cdc2-like kinases (Clks), pre-mRNAprocessing mutant 4 (PRP4), and topoisomerase I. Optimal phosphorylationof SR proteins may be required for proper functioning as both hypo- andhyperphosphorylation of the RS domains may be detrimental to their rolein constitutive and alternative splicing.

In higher eukaryotes, the vast majority of genes contain one or moreintrons, which creates a situation in which the exons are splicedtogether to generate mature mRNA and microRNA (miRNA). In the hostnucleus, pre-mRNA splicing is the mechanism by which introns are removedfrom a pre-mRNA and the exons are ligated together to generate maturemRNAs and pre-miRNA that is then exported to the cytoplasm fortranslation into the polypeptide gene product. Splicing of pre-mRNA canoccur in cis, where two exons derive from two adjacent cotranscribedsequences, or in trans, when the two exons come from different pre-mRNAtranscripts. The ratio of the different protein products (isoforms) maybe due to the frequency of alternative splicing events within a pre-mRNAthat leads to different amounts of distinct splice variants. In someembodiments, alternative splicing of a pre-mRNA may lead to 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 proteinisoforms being expressed.

Aberrations in splicing are thought to be the cause of roughly half ofall inherited diseases. Aberrant splicing due to mutations in consensussequences involved in exon-intron boundary recognition is responsiblefor up to 15% of inherited diseases. In addition, defects in thesplicing machinery itself due to the loss or gain of function ofsplicing factors and modulators are causes of a wide range of humanailments from cancer to neurodegenerative diseases. Both constitutiveand alternative splicing are subject to regulation by upstream signalingpathways. This regulation can be essential during development, in tissuespecific expression of certain isoforms, during the cell cycle and inresponse to extrinsic signaling molecules.

Alternative splicing allows for a single gene to express differentisoforms of mRNA, thus playing a major role in contributing to thecellular complexity in higher eukaryotes without the need to expand thegenome. Splicing can also be subject to regulation by upstream signalingpathways. For example, an upstream signaling pathway may modulatealternative splicing and increase or decrease expression levels ofdifferent isoforms of mRNA.

Alternative splicing events are highly regulated by numerous splicingfactors in a tissue type-, developmental stage-, and signal-dependentmanner. Furthermore, non-mutation based causes of splicing defects anddefects in the splicing machinery itself, e.g., due to the loss/gain offunction of splicing factors or their relative stoichiometry, cause of awide range of human ailments, ranging from cancer to neurodegenerativediseases. In many diseases the disease state is caused by an alterationof the ratio of different isoforms of two or more proteins expressedfrom a gene. In some embodiments, the alteration in the ratio of theprotein products is due to changes in the frequency of alternativesplicing events within a pre-mRNA, leading to changes in the ratio ofsplice variants produced. In some embodiments, alternative splicing of apre-mRNA may lead to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19 or 20 protein isoforms being expressed. In some embodiments,a change in the splice variant ratio is caused by genetic mutation.

In eukaryotes, the vast majority of splicing processes are catalyzed bythe spliceosome, an RNA-protein complex that occurs in unique steps andmay comprise a subset of several hundred different proteins, in additionto five spliceosomal snRNAs. These factors are responsible for theaccurate positioning of the spliceosome on the 5′ and 3′ splice sitesequences. The reason why so many factors are needed reflects theobservation that exon recognition can be affected by many pre-mRNAfeatures such as exon length, sequence recognition, the presence ofenhancer and silencer elements, the strength of upstream splicingsignals, the promoter architecture, and the rate of RNA processivity,secondary and tertiary RNA structure.

All mammalian diseases are ultimately mediated by the transcriptome.Insofar as messenger mRNA (mRNA) is part of the transcriptome, and allprotein expression derives from mRNAs, there is the potential tointervene in protein-mediated diseases by modulating the expression ofthe relevant protein and by, in turn, modulating the translation of thecorresponding upstream mRNA. But mRNA is only a small portion of thetranscriptome: other transcribed RNAs also regulate cellular biologyeither directly by the structure and function of RNA structures (e.g.,ribonucleoproteins) as well as via protein expression and action,including (but not limited to) microRNA (miRNA), long noncoding RNA(lncRNA), long intergenic noncoding RNA (lincRNA), small nucleolar RNA(snoRNA), small nuclear RNA (snRNA), small Cajal body-specific RNA(scaRNA), piwi-interacting RNA (piRNA), competing endogenous (ceRNA),and pseudo-genes. Drugs that intervene at this level have the potentialof modulating any and all cellular processes. Existing therapeuticmodalities such as antisense RNA or siRNA, in most cases, have yet toovercome significant challenges such as drug delivery, absorption,distribution to target organs, pharmacokinetics, and cell penetration.In contrast, small molecules have a long history of successfullysurmounting these barriers and these qualities, which make them suitableas drugs, are readily optimized through a series of analogues toovercome such challenges. In sharp contrast, the application of smallmolecules as ligands for RNA that yield therapeutic benefit has receivedlittle to no attention from the drug discovery community.

DNA sequences in the chromosome are transcribed into pre-mRNAs whichcontain coding regions (exons) and generally also contain interveningnon-coding regions (introns). Introns are removed from pre-mRNAs throughsplicing. Pre-mRNA splicing proceeds by a two-step mechanism. In thefirst step, the 5′ splice site is cleaved, resulting in a “free” 5′ exonand a lariat intermediate. In the second step, the 5′ exon is ligated tothe 3′ exon with release of the intron as the lariat product. Thesesteps are catalyzed in a complex of small nuclear ribonucleoproteins andproteins called the spliceosome.

In most cases, the splicing reaction occurs within the same pre-mRNAmolecule, which is termed cis-splicing. Splicing between twoindependently transcribed pre-mRNAs is termed trans-splicing.

Introns are portions of eukaryotic DNA, which intervene between thecoding portions, or “exons,” of that DNA. Introns and exons aretranscribed into RNA termed “primary transcript, precursor to mRNA” (or“pre-mRNA”). Introns can be removed from the pre-mRNA so that the nativeprotein encoded by the exons can be produced (the term “native protein”as used herein refers to naturally occurring, wild type, or functionalprotein). The removal of introns from pre-mRNA and subsequent joining ofthe exons is carried out in the splicing process.

The splicing process is a series of reactions, which are carried out onRNA after transcription but before translation and which are mediated bysplicing factors. Thus, a “pre-mRNA” can be an RNA that contains bothexons and intron(s), and a mature mRNA (“mRNA”) can be an RNA in whichthe intron(s) have been removed and the exons joined togethersequentially so that the protein may be translated therefrom by theribosomes.

Introns can be defined by a set of “splice elements” that are part ofthe splicing machinery and may be required for splicing and which arerelatively short, conserved RNA segments that bind the various splicingfactors, which carry out the splicing reactions. Thus, each intron isdefined by a 5′ splice site, a 3′ splice site, and a branch pointsituated there between. Splice elements also comprise exon splicingenhancers and silencers, situated in exons, and intron splicingenhancers and silencers situated in introns at a distance from thesplice sites and branch points. In addition to splice site and branchpoints these elements control alternative aberrant and constitutivesplicing.

Initial RNA transcripts (pre-mRNA) of most eukaryotic genes are retainedin the nucleus until non-coding intron sequences are removed by thespliceosome to produce mature messenger RNA (mRNA). The splicing thatoccurs can vary, so the synthesis of alternative protein products fromthe same primary transcript can be affected by tissue-specific ordevelopmental signals. A significant fraction of human genetic diseases,including a number of cancers, are believed to result from deviations inthe normal pattern of pre-mRNA splicing. The spliceosome is a complexcomprising ribonucleoprotein (snRNP) particles composed of small nuclearRNAs and proteins. snRNA components of the spliceosome can promote thetwo transesterification reactions of splicing.

Two unique spliceosomes coexist in most eukaryotes: the U2-dependentspliceosome, which catalyzes the removal of U2-type introns, and theless abundant U12-dependent spliceosome, which is present in only asubset of eukaryotes and splices the rare U12-type class of introns. TheU2-dependent spliceosome is assembled from the U1, U2, U5, and U4/U6snRNPs and numerous non-snRNP proteins. The U2 snRNP is recruited withtwo weakly bound protein subunits, SF3a and SF3b, during the firstATP-dependent step in spliceosome assembly. SF3b is composed of sevenconserved proteins, including PHF5a, SF3b155, SF3b145, SF3b130, SF3b49,SF3b14a, and SF3b10.

Splicing or RNA splicing typically refers to the editing of the nascentprecursor messenger RNA (pre-mRNA) transcript into a mature messengerRNA (mRNA). Splicing is a biochemical process which includes the removalof introns followed by exon ligation. Sequential transesterificationreactions are initiated by a nucleophilic attack of the 5′ splice site(5′ss) by the branch adenosine (branch point; BP) in the downstreamintron resulting in the formation of an intron lariat intermediate witha 2′,5′-phosphodiester linkage. This is followed by a 5′ss-mediatedattack on the 3′ splice site (3′ss), leading to the removal of theintron lariat and the formation of the spliced RNA product.

Splicing can be regulated by various cis-acting elements andtrans-acting factors. Cis-acting elements are sequences of the mRNA andcan include core consensus sequences and other regulatory elements. Coreconsensus sequences typically can refer to conserved RNA sequencemotifs, including the 5′ss, 3′ss, polypyrimidine tract and BP region,which can function for spliceosome recruitment. BP refers to a partiallyconserved sequence of pre-mRNA, generally less than 50 nucleotidesupstream of the 3′ss. BP reacts with the 5′ss during the first step ofthe splicing reaction. Other regulatory cis-acting elements can includeexonic splicing enhancer (ESE), exonic splicing silencer (ESS), intronicsplicing enhancer (ISE), and intronic splicing silencer (ISS).Trans-acting factors can be proteins or ribonucleoproteins which bind tocis-acting elements.

Splice site identification and regulated splicing can be accomplishedprincipally by two dynamic macromolecular machines, the major(U2-dependent) and minor (U12-dependent) spliceosomes. Each spliceosomecontains five snRNPs: U1, U2, U4, U5 and U6 snRNPs for the majorspliceosome (which processes 95.5% of all introns); and U11, U12,U4atac, U5 and U6 atac snRNPs for the minor spliceosome. Spliceosomerecognition of consensus sequence elements at the 5′ss, 3′ss and BPsites is one of the steps in the splicing pathway, and can be modulatedby ESEs, ISEs, ESSs, and ISSs, which can be recognized by auxiliarysplicing factors, including SR proteins and hnRNPs. Polypyrimidinetract-binding protein (PTBP) can bind to the polypyrimidine tract ofintrons and may promote RNA looping.

Alternative splicing is a mechanism by which a single gene mayeventually give rise to several different proteins. Alternative splicingcan be accomplished by the concerted action of a variety of differentproteins, termed “alternative splicing regulatory proteins,” thatassociate with the pre-mRNA, and cause distinct alternative exons to beincluded in the mature mRNA. These alternative forms of the gene'stranscript can give rise to distinct isoforms of the specified protein.Sequences in pre-mRNA molecules that can bind to alternative splicingregulatory proteins can be found in introns or exons, including, but notlimited to, ISS, ISE, ESS, ESE, and polypyrimidine tract. Many mutationscan alter splicing patterns. For example, mutations can be cis-actingelements, and can be located in core consensus sequences (e.g. 5′ss,3′ss and BP) or the regulatory elements that modulate spliceosomerecruitment, including ESE, ESS, ISE, and ISS.

A cryptic splice site, for example, a cryptic 5′ss and a cryptic 3′ss,can refer to a splice site that is not normally recognized by thespliceosome and therefore are in the dormant state. Cryptic splice sitecan be recognized or activated, for example, by mutations in cis-actingelements or trans-acting factors, or structural configurations, such asbulges.

Splicing Modulation

The present invention contemplates use of small molecules with favorabledrug properties that modulate the activity of splicing of a target RNA.Provided herein are small molecule splicing modulators (SMSMs) thatmodulate splicing of a target polynucleotide. In some embodiments, theSMSMs bind and modulate target RNA. In some embodiments, provided hereinis a library of SMSMs that bind and modulate one or more target RNAs. Insome embodiments, the target RNA is mRNA. In some embodiments, thetarget RNA is mRNA a noncoding RNA. In some embodiments, the target RNAis a pre-mRNA. In some embodiments, the target RNA is hnRNA. In someembodiments, the small molecules modulate splicing of the target RNA. Insome embodiments, a small molecule provided herein modulates splicing ata sequence of the target RNA. In some embodiments, a small moleculeprovided herein modulates splicing at a cryptic splice site sequence ofthe target RNA. In some embodiments, a small molecule provided hereinbinds to a target RNA. In some embodiments, a small molecule providedherein binds to a splicing complex component. In some embodiments, asmall molecule provided herein binds to a target RNA and a splicingcomplex component.

Thus, provided herein are methods of preventing or inducing a splicingevent in a pre-mRNA molecule, comprising contacting the pre-mRNAmolecule and/or other elements of the splicing machinery (e.g., within acell) with a compound provided herein to prevent or induce the splicingevent in the pre-mRNA molecule. The splicing event that is prevented orinduced can be, e.g., an aberrant splicing event, a constitutivesplicing event or an alternate splicing event.

Further provided herein is a method of identifying a compound capable ofpreventing or inducing a splicing event in a pre-mRNA molecule,comprising contacting the compound with splicing elements and/or factorsinvolved in alternative, aberrant and/or constitutive splicing asdescribed herein (e.g., within cells) under conditions whereby apositive (prevention or induction of splicing) or negative (noprevention or induction of splicing) effect is produced and detected andidentifying a compound that produces a positive effect as a compoundcapable of preventing or inducing a splicing event.

In some embodiments, a small molecule compound described herein in apharmaceutically acceptable carrier prevents or induces an alternativeor aberrant splicing event in a pre-mRNA molecule. As noted above, thesmall molecule compounds provided herein are not antisense or antigeneoligonucleotides. Tables 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 1J, 1K, 1L, and1M show the chemical structure and name of exemplary compounds and arenot intended to be all-inclusive.

In some embodiments, a composition comprises a small molecule splicingmodulator compound (SMSM); wherein the SMSM interacts with an unpairedbulged nucleobase of an RNA duplex, and wherein the RNA duplex comprisesa splice site. Provided herein is composition comprising a complexcomprising a small molecule splicing modulator compound (SMSM) bound toan RNA duplex, wherein the SMSM interacts with an unpaired bulgednucleobase of an RNA duplex, and wherein the RNA duplex comprises asplice site. In some embodiments, the duplex RNA comprises an alphahelix. In some embodiments, the unpaired bulged nucleobase is located onan external portion of a helix of the duplex RNA. In some embodiments,the unpaired bulged nucleobase is located within an internal portion ofthe helix of the duplex RNA. In some embodiments, the SMSM forms one ormore intermolecular interactions with the duplex RNA. In someembodiments, the SMSM forms one or more intermolecular interactions withthe unpaired bulged nucleobase. In some embodiments, the intermolecularinteraction is selected from the group comprising an ionic interaction,a hydrogen bond, a dipole-dipole interaction or a van der Waalsinteraction. In some embodiments, a first portion of the SMSM interactswith the unpaired bulged nucleobase on a first RNA strand of the RNAduplex. In some embodiments, a second portion of the SMSM interacts withone or more nucleobases of a second RNA strand of the RNA duplex,wherein the first RNA strand is not the second RNA strand. In someembodiments, a rate of exchange of the unpaired bulged nucleobase fromwithin the interior of a helix of the duplex RNA to an exterior portionof the helix is reduced. In some embodiments, the SMSM reduces a rate ofrotation of the unpaired bulged nucleobase. In some embodiments, theSMSM reduces a rate of rotation of the unpaired bulged nucleobase arounda phosphate backbone of an RNA strand of the RNA duplex. In someembodiments, the SMSM modulates a distance of the unpaired bulgednucleobase from a second nucleobase of the duplex RNA. In someembodiments, the SMSM reduces the distance of the unpaired bulgednucleobase from a second nucleobase of the duplex RNA. In someembodiments, the unpaired bulged nucleobase is located within theinterior of a helix of the duplex RNA of the complex. In someembodiments, the SMSM reduces a size of a bulge of the RNA duplex. Insome embodiments, the SMSM removes a bulge of the RNA duplex. In someembodiments, the SMSM stabilizes a bulge of the RNA duplex. In someembodiments, the SMSM modulates splicing at the splice site of the RNAduplex. In some embodiments, the SMSM increases splicing at the splicesite of the RNA duplex. In some embodiments, the SMSM reduces splicingat the splice site of the RNA duplex. In some embodiments, the unpairedbulged nucleobase has modulated base stacking within an RNA strand ofthe RNA duplex. In some embodiments, the unpaired bulged nucleobase hasincreased base stacking within an RNA strand of the RNA duplex. In someembodiments, the unpaired bulged nucleobase has decreased base stackingwithin an RNA strand of the RNA duplex. In some embodiments, the SMSM isnot an aptamer. In some embodiments, the RNA duplex comprises pre-mRNA.In some embodiments, the unpaired bulged nucleobase is free to rotatearound a phosphate backbone of an RNA strand of the RNA duplex in theabsence of the SMSM.

In some embodiments, a method of modulating splicing comprisescontacting a small molecule splicing modulator compound (SMSM) to cells,wherein the SMSM kills the cells at an IC₅₀ of less than 50 nM. In someembodiments, a method of modulating splicing comprises contacting asmall molecule splicing modulator compound (SMSM) to cells, wherein theSMSM modulates splicing at a splice site sequence of a pre-mRNA thatencodes a mRNA, wherein the mRNA encodes a target protein or afunctional RNA, and wherein a total amount of the mRNA is increased atleast about 10% compared to the total amount of the mRNA encoding thetarget protein or functional RNA produced in control cells. In someembodiments, a method of modulating splicing comprises contacting asmall molecule splicing modulator compound (SMSM) to cells, wherein theSMSM modulates splicing at a splice site sequence of a pre-mRNA thatencodes a mRNA, wherein the mRNA encodes a target protein or afunctional RNA, and wherein a total amount of the mRNA, the targetprotein and/or the functional RNA is at least 10% lower than the totalamount of the mRNA, the target protein and/or the functional RNA incontrol cells.

In some embodiments, a method of modulating splicing comprisescontacting a small molecule splicing modulator compound (SMSM) to cells,wherein the SMSM modulates splicing at a splice site sequence of apre-mRNA that encodes a first mRNA isoform associated with a disease orcondition and a second mRNA isoform, wherein a total amount of the firstmRNA isoform is decreased by at least about 10% compared to the totalamount of the first mRNA isoform in control cells, and/or a total amountof the second mRNA isoform is increased by at least about 10% comparedto the total amount of the first mRNA isoform in control cells. In someembodiments, a method of modulating splicing comprises contacting asmall molecule splicing modulator compound (SMSM) to cells comprising anamount of a first mRNA isoform and an amount of a second mRNA isoformpresent in the cells; wherein a ratio of the first mRNA isoform to thesecond mRNA isoform is decreased at least 1.2 fold; wherein the firstand second mRNAs are encoded by a pre-MRNA comprising a splice sitesequence, and wherein the first mRNA isoform is associated with adisease or condition and a second mRNA isoform.

In some embodiments, a method of modulating splicing comprisescontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, wherein theSMSM modulates exon inclusion, exon exclusion, pseudoexon inclusion,intron retention, or splicing at a cryptic splice site of thepolynucleotide, and wherein the SMSM modulates splicing of the splicesite sequence. In some embodiments, a method of modulating splicingcomprises contacting a small molecule splicing modulator compound (SMSM)to a cell comprising a polynucleotide with a splice site sequence,thereby modulating splicing of the polynucleotide, wherein the splicesite sequence comprises a splice site sequence selected from the groupconsisting of splice site sequences Table 2A, Table 2B, Table 2C orTable 2D. In some embodiments, a method of modulating splicing comprisescontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, wherein thesplice site sequence comprises a sequence selected from GGAguaag andAGAguaag. In some embodiments, a method of modulating splicing comprisescontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, wherein thesplice site sequence comprises at least one bulged nucleotide at the −3,−2, −1, +1, +2, +3, +4, +5 or +6 position of the splice site sequence.In some embodiments, a method of modulating splicing comprisescontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, wherein thesplice site sequence comprises a mutant nucleotide at the −3, −2, −1,+1, +2, +3, +4, +5 or +6 position of the splice site sequence.

In some embodiments, a method of modulating splicing comprisescontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, therebymodulating splicing of the polynucleotide, wherein the splice sitesequence comprises a sequence selected from the group consisting ofNGAgunvrn, NHAdddddn, NNBnnnnnn, and NHAddmhvk; wherein N or n is A, U,G or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is aor c; r is a or g; v is a, c or g; k is g or u. In some embodiments, amethod of modulating splicing comprises contacting a small moleculesplicing modulator compound (SMSM) to a cell comprising a polynucleotidewith a splice site sequence, thereby modulating splicing of thepolynucleotide, wherein the splice site sequence comprises a sequenceselected from the group consisting of NNBgunnnn, NNBhunnnn, orNNBgvnnnn; wherein N or n is A, U, G or C; B is C, G, or U; H or h is A,C, or U; d is a, g, or u; m is a or c; r is a or g; v is a, c or g; k isg or u. In some embodiments, the splice site sequence comprises asequence selected from the group consisting of NNBgurrrn, NNBguwwdn,NNBguvmvn, NNBguvbbn, NNBgukddn, NNBgubnbd, NNBhunngn, NNBhurmhd, orNNBgvdnvn; wherein N or n is A, U, G or C; B is C, G, or U; H or h is A,C, or U; d is a, g, or u; m is a or c; r is a or g; v is a, c or g; k isg or u. In some embodiments, the nucleotide at the −3, −2, −1, +1, +2,+3, +4, +5 or +6 position of the splice site sequence is a bulgednucleotide. In some embodiments, the nucleotide at the −3, −2, −1, +1,+2, +3, +4, +5 or +6 position of the splice site sequence is mutatednucleotide. In some embodiments, the splice site sequence comprises asequence selected from the group consisting of splice site sequences ofTable 2A, Table 2B, Table 2C or Table 2D.

In some embodiments, a method of modulating splicing comprisescontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, therebymodulating splicing of the polynucleotide, wherein the polynucleotide isencoded by a gene selected from the group consisting of genes of Table2A, Table 2B, Table 2C or Table 2D. In some embodiments, the gene isSMN2. In some embodiments, modulating splicing of the polynucleotidecomprises inhibiting skipping of exon 7. In some embodiments, the geneis DMD. In some embodiments, modulating splicing of the polynucleotidecomprises promoting skipping of exon 51.

In some embodiments, a method of modulating splicing comprisescontacting a small molecule splicing modulator compound (SMSM) to acell; wherein the SMSM interacts with an unpaired bulged nucleobase ofan RNA duplex in the cell; wherein the duplex RNA comprises a splicesite sequence; and wherein the SMSM modulates splicing of the RNAduplex. In some embodiments, a method comprises modulating the relativeposition of a first nucleobase relative to a second nucleobase, whereinthe first nucleobase and the second nucleobase are within a duplex RNA,the method comprising contacting a small molecule splicing modulatorcompound (SMSM) to the duplex RNA, or a pharmaceutically acceptable saltthereof, wherein the first nucleobase is an unpaired bulged nucleobaseof the RNA duplex; wherein the duplex RNA comprises a splice sitesequence.

In some embodiments, the duplex RNA comprises a helix. In someembodiments, the unpaired bulged nucleobase is located on an externalportion of a helix of the duplex RNA prior to contacting the SMSM. Insome embodiments, the SMSM forms one or more intermolecular interactionswith the duplex RNA. In some embodiments, the SMSM forms one or moreintermolecular interactions with the unpaired bulged nucleobase. In someembodiments, the intermolecular interaction is selected from the groupcomprising an ionic interaction, a hydrogen bond, a dipole-dipoleinteraction or a van der Waals interaction. In some embodiments, a rateof exchange of the unpaired bulged nucleobase from within the interiorof a helix of the duplex RNA to an exterior portion of the helix isreduced. In some embodiments, a rate of rotation of the unpaired bulgednucleobase is reduced. In some embodiments, a rate of rotation of theunpaired bulged nucleobase around a phosphate backbone of an RNA strandof the RNA duplex is reduced. In some embodiments, a distance of theunpaired bulged nucleobase from a second nucleobase of the duplex RNA ismodulated after contacting the SMSM. In some embodiments, the distanceof the unpaired bulged nucleobase from a second nucleobase of the duplexRNA is reduced. In some embodiments, the unpaired bulged nucleobase islocated within the interior of the helix of the duplex RNA. In someembodiments, a size of a bulge of the RNA duplex is reduced. In someembodiments, a bulge of the RNA duplex is removed or maintained. In someembodiments, splicing at the splice site of the RNA duplex is promoted.In some embodiments, base stacking of the unpaired bulged nucleobasewithin an RNA strand of the RNA duplex is increased after contacting theSMSM. In some embodiments, the distance of the unpaired bulgednucleobase from a second nucleobase of the duplex RNA is increased ormaintained. In some embodiments, a bulge of the RNA duplex is stabilizedafter contacting the SMSM. In some embodiments, the unpaired bulgednucleobase is located on an exterior portion of a helix of the duplexRNA. In some embodiments, a size of a bulge of the RNA duplex isincreased. In some embodiments, splicing at the splice site of the RNAduplex is inhibited. In some embodiments, splicing is inhibited at thesplice site In some embodiments, base stacking of the unpaired bulgednucleobase within an RNA strand of the RNA duplex is reduced aftercontacting the SMSM. In some embodiments, the RNA duplex comprisespre-mRNA.

In some embodiments, a method of treating a subject with a tumorcomprises administering a small molecule splicing modulator compound(SMSM) to the subject, wherein a size of the tumor is reduced. In someembodiments, a method of treating a subject with a tumor comprisesadministering a small molecule splicing modulator compound (SMSM) to thesubject, wherein tumor growth is inhibited by at least 20. In someembodiments, a method of the treatment, prevention and/or delay ofprogression of a condition or disease comprises administering a smallmolecule splicing modulator compound (SMSM) to a subject, wherein theSMSM modulates splicing of a splice site of a polynucleotide in a cellof the subject, wherein the condition or disease is associated withsplicing of the splice site. In some embodiments, the subject has thedisease or condition. In some embodiments, a method of treating asubject with a disease or condition comprises administering a smallmolecule splicing modulator compound (SMSM) to a subject with a diseaseor condition selected from the group consisting of diseases of Table 2A,Table 2B, Table 2C or Table 2D. In some embodiments, a method oftreating a subject with a disease or condition comprises administering asmall molecule splicing modulator compound (SMSM) to a subject with adisease or condition, wherein the SMSM is selected from the groupconsisting of the SMSMs of Tables 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 1J,1K, 1L, and 1M. In some embodiments, a method of treating a subject witha disease or condition comprises administering a small molecule splicingmodulator compound (SMSM) to a subject with a disease or condition,wherein the SMSM binds to a pre-mRNA comprising a splice site sequenceselected from the group consisting of splice site sequences of Table 2A,Table 2B, Table 2C or Table 2D. In some embodiments, the subject is amammal. In some embodiments, the mammal is a human. In some embodiments,the polynucleotide is a pre-mRNA. In some embodiments, the disease orcondition is spinal muscular atrophy. In some embodiments, the diseaseor condition is Duchenne's muscular dystrophy. In some embodiments, themethod further comprises administering an additional therapeuticmolecule to the subject. In some embodiments, the SMSM is a compounddescribed herein. In some embodiments, the SMSM is selected from thegroup consisting of SMSMs of Tables 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 1J,1K, 1L, and 1M.

In some embodiments, modulating splicing comprises preventing,inhibiting or reducing splicing at the splice site sequence of thepolynucleotide. In some embodiments, modulating splicing comprisesenhancing, promoting or increasing splicing at the splice site sequenceof the polynucleotide. In some embodiments, the splice site sequence isa 5′ splice site sequence, a 3′ splice site sequence, a branch pointsplice site sequence or a cryptic splice site sequence. In someembodiments, the splice site comprises a mutation, the splice sitecomprises a bulge, the splice site comprises a mutation and a bulge, thesplice site does not comprises a mutation, the splice site does notcomprises a bulge, or the splice site does not comprises a mutation anddoes not comprise a bulge. In some embodiments, the bulge is a bulgecaused by the mutation. In some embodiments, a bulged nucleotide is amutant nucleotide. In some embodiments, a bulged nucleotide is not amutant nucleotide. In some embodiments, the SMSM decreases a K_(D) ofsplicing complex component to the polynucleotide. In some embodiments,the SMSM increases a K_(D) of splicing complex component to thepolynucleotide. In some embodiments, the SMSM inhibits binding of asplicing complex component to the polynucleotide at the splice sitesequence, upstream of the splice site sequence or downstream of thesplice site sequence. In some embodiments, the SMSM promotes binding ofa splicing complex component to the polynucleotide at the splice sitesequence, upstream of the splice site sequence or downstream of thesplice site sequence. In some embodiments, the polynucleotide is RNA. Insome embodiments, the RNA is a pre-mRNA. In some embodiments, the RNA isa heterogeneous nuclear RNA. In some embodiments, the splice sitesequence is a 5′ splice site sequence, a 3′ splice site sequence, abranch point (BP) splice site sequence, an exonic splicing enhancer(ESE) sequence, an exonic splicing silencer (ESS) sequence, an intronicsplicing enhancer (ISE) sequence, an intronic splicing silencer (ISS)sequence, a polypyrimidine tract sequence, or any combination thereof.In some embodiments, the polynucleotide is at least 5, 6, 7, 8, 9, 10,15, 20, 25, 50, 100, 250, 500, 750, 1,000, 2,000, 5,000, 10,000, 50,000,100,000, 500,000, or 1,000,000 nucleotides in length. In someembodiments, the SMSM binds to the splice site sequence of thepolynucleotide. In some embodiments, the SMSM interacts with a bulge ofthe splice site sequence of the polynucleotide. In some embodiments, thepolynucleotide comprises a cis-acting element sequence. In someembodiments, the cis-acting element sequence does not comprise a bulge.In some embodiments, the cis-acting element sequence does not comprise amutation. In some embodiments, the cis-acting element sequence comprisesa mutation, a bulge, or a combination thereof, at the cis-acting elementsequence, 1-1000 nucleobases upstream of the cis-acting element sequenceor 1-1000 nucleobases downstream of the cis-acting element sequence. Insome embodiments, the cis-acting element sequence comprises a regulatoryelement sequence that modulates recruitment of a splicing complexcomponent to the polynucleotide. In some embodiments, the cis-actingelement sequence comprises a regulatory element sequence that modulatesrecruitment of a spliceosome to the polynucleotide. In some embodiments,the regulatory element sequence comprises an exonic splicing enhancer(ESE) sequence, an exonic splicing silencer (ESS) sequence, an intronicsplicing enhancer (ISE) sequence, an intronic splicing silencer (ISS)sequence, and combinations thereof. In some embodiments, the SMSM bindsto the splicing complex component. In some embodiments, the splicingcomplex component is 9G8, A1 hnRNP, A2 hnRNP, ASD-1, ASD-2b, ASF, B1hnRNP, C1 hnRNP, C2 hnRNP, CBP20, CBP80, CELF, F hnRNP, FBP11, Fox-1,Fox-2, G hnRNP, H hnRNP, hnRNP 1, hnRNP 3, hnRNP C, hnRNP G, hnRNP K,hnRNP M, hnRNP U, Hu, HUR, I hnRNP, K hnRNP, KH-type splicing regulatoryprotein (KSRP), L hnRNP, M hnRNP, mBBP, muscle-blind like (MBNL), NF45,NFAR, Nova-1, Nova-2, nPTB, P54/SFRS11, polypyrimidine tract bindingprotein (PTB), PRP19 complex proteins, R hnRNP, RNPC1, SAM68, SC35, SF,SF1/BBP, SF2, SF3 a, SF3B, SFRS10, Sm proteins, SR proteins, SRm300,SRp20, SRp30c, SRP35C, SRP36, SRP38, SRp40, SRp55, SRp75, SRSF, STAR,GSG, SUP-12, TASR-1, TASR-2, TIA, TIAR, TRA2, TRA2a/b, U hnRNP, U1snRNP, U11 snRNP, U12 snRNP, U1-C, U2 snRNP, U2AF1-RS2, U2AF35, U2AF65,U4 snRNP, U5 snRNP, U6 snRNP, Urp, YB1, or any combination thereof. Insome embodiments, the splicing complex component comprises RNA. In someembodiments, the splicing complex component is a small nuclear RNA(snRNA). In some embodiments, the snRNA comprises U1 snRNA, U2 snRNA, U4snRNA, U5 snRNA, U6 snRNA, U11 snRNA, U12 snRNA, U4atac snRNA, U5 snRNA,U6 atac snRNA, or any combination thereof. In some embodiments, thesplicing complex component comprises a protein. In some embodiments, thesplicing complex component comprises a small nuclear ribonucleoprotein(snRNP). In some embodiments, the snRNP comprises U1 snRNP, U2 snRNP, U4snRNP, U5 snRNP, U6 snRNP, U11 snRNP, U12 snRNP, U4atac snRNP, U5 snRNP,U6 atac snRNP, or any combinations thereof. In some embodiments, theprotein is a serine/arginine-rich (SR) protein. In some embodiments, thesplice site sequence comprises a base that is mismatched to a base of asnRNA sequence. In some embodiments, a bulge is due to mismatched basepairing between the splice site sequence and a snRNA sequence.

In some embodiments, a method comprises upregulating expression of anative protein in a cell containing a DNA encoding the native protein,wherein the DNA contains a mutation or no mutation that causesdownregulation of the native protein by aberrant and/or alternatesplicing thereof. For example, the DNA can encode a pre-mRNA that has amutation or an aberrant secondary or tertiary structure that causesdownregulation of one or more isoforms of a protein. The method cancomprise introducing into the cell a small molecule provided herein thatprevents an aberrant splicing event, whereby the native intron isremoved by correct splicing and the native protein is produced by thecell. In some embodiments, a method comprises introducing into a cell asmall molecule provided herein that modulates an alternate splicingevent to produce a protein that has a different function than theprotein that would be produced without modulation of alternate splicing.

In some embodiments, a method comprises downregulating expression of anative protein in a cell containing a DNA encoding the native protein,wherein the DNA contains a mutation or no mutation that causesupregulation of the native protein by aberrant and/or alternate splicingthereof. For example, the DNA can encode a pre-mRNA that has a mutationor an aberrant secondary or tertiary structure that causes upregulationof one or more isoforms of a protein. The method can compriseintroducing into the cell a small molecule provided herein that preventsan aberrant splicing event, whereby the native intron is removed bycorrect splicing and the native protein is produced by the cell. In someembodiments, a method comprises introducing into a cell a small moleculeprovided herein that modulates an alternate splicing event to produce aprotein that has a different function than the protein that would beproduced without modulation of alternate splicing. For example, a methodcan comprise preventing aberrant splicing in a pre-mRNA moleculecontaining a mutation or an aberrant secondary or tertiary structureand/or preventing an alternative splicing event. When present in thepre-mRNA, the mutation or aberrant secondary or tertiary structure cancause a pre-mRNA to splice incorrectly and produce an aberrant mRNA ormRNA fragment different from the mRNA ordinarily resulting from apre-mRNA without the mutation or aberrant secondary or tertiarystructure. For example, s pre-mRNA molecule can contain: (i) a first setof splice elements defining a native intron which can be removed bysplicing when the mutation or aberrant secondary or tertiary structureis absent to produce a first mRNA molecule encoding a native protein,and (ii) a second set of splice elements induced by the mutation oraberrant secondary or tertiary structure which defines an aberrantintron different from the native intron, which aberrant intron isremoved by splicing when the mutation or aberrant secondary or tertiarystructure is present to produce an aberrant second mRNA moleculedifferent from the first mRNA molecule. The method can comprisecontacting the pre-mRNA molecule and/or other factors and/or elements ofthe splicing machinery as described herein (e.g., within a cell) with acompound described herein to prevent or promote an aberrant splicingevent in a pre-mRNA molecule, whereby the native intron is removed bycorrect splicing and native protein production is increased in the cell.

In some embodiments, a method comprises upregulating expression of a RNAthat would otherwise be downregulated by modulating an alternativesplicing event in the RNA. The method can comprise contacting a pre-mRNAmolecule and/or other elements and/or factors of the splicing machinerywith a compound described herein to modulate alternate splicing events,whereby a native splicing event is inhibited and an alternate splicingevent is promoted that upregulates expression of a RNA that is otherwisedownregulated when under the control of the native splicing event.

In some embodiments, a method comprises downregulating expression of aRNA that would otherwise be upregulated by modulating an alternativesplicing event in the RNA. The method can comprise contacting a pre-mRNAmolecule and/or other elements and/or factors of the splicing machinerywith a compound described herein to modulate alternate splicing events,whereby a native splicing event is inhibited and an alternate splicingevent is promoted that downregulates expression of a RNA that isotherwise upregulated when under the control of the native splicingevent.

The methods, compounds and compositions described herein have a varietyof uses. For example, they are useful in any process where it is desiredto have a means for downregulating expression of a RNA to be expresseduntil a certain time, after which it is desired to upregulate RNAexpression. For such use, the RNA to be expressed may be any RNAencoding a protein to be produced so long as the gene contains a nativeintron. The RNA may be mutated by any suitable means, such assite-specific mutagenesis (see, T. Kunkel, U.S. Pat. No. 4,873,192) todeliberately create an aberrant second set of splice elements whichdefine an aberrant intron which substantially downregulates expressionof the gene. A sequence encoding the RNA may be inserted into a suitableexpression vector and the expression vector inserted into a host cell(e.g., a eukaryotic cell such as a yeast, insect, or mammalian cell(e.g., human, rat)) by standard recombinant techniques. The host cellcan then be grown in culture by standard techniques. When it is desiredto upregulate expression of the mutated gene, a suitable compound of thepresent invention, in a suitable formulation, can be added to theculture medium so that expression of the gene is upregulated.

Also provided herein is a method of altering the ratio of splicevariants produced from a gene. The method can comprise contacting apre-mRNA molecule and/or other elements and/or factors of the splicingmachinery with a compound or compounds described herein to modulatealternative splicing events. The compound or compounds of this inventioncan be used to act upon 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19 or 20 alternative splicing events that may occurwithin a pre-mRNA. In some embodiments, a first splice variant may bedownregulated or inhibited and/or a second splice variant may beupregulated, resulting in an altered ratio of splice variants of the twoor more RNA. In some embodiments, a first splice variant may beupregulated while a second splice variant may be unaffected, therebyaltering the ratio of the RNA. In some embodiments, a first splicevariant may be downregulated while a second splicing event may beunaffected thereby altering the ratio of the RNA.

The methods, compounds and formulations described herein are also usefulas in vitro or in vivo tools to examine and modulate splicing events inhuman or animal RNAs encoded by genes, e.g., those developmentallyand/or tissue regulated (e.g., alternate splicing events).

The compounds and formulations described herein are also useful astherapeutic agents in the treatment of disease involving aberrant and/oralternate splicing. Thus, in some embodiments, a method of treating asubject having a condition or disorder associated with an alternative oraberrant splicing event in a pre-mRNA molecule, comprises administeringto the subject a therapeutically effective amount of a compounddescribed herein to modulate an alternative splicing event or prevent anaberrant splicing event, thereby treating the subject. The method can,e.g., restore a correct splicing event in a pre-mRNA molecule. Themethod can, e.g., utilize a small molecule compound described herein ina pharmaceutically acceptable carrier.

Formulations containing the small molecules described herein cancomprise a physiologically or pharmaceutically acceptable carrier, suchas an aqueous carrier. Thus, formulations for use in the methodsdescribed herein include, but are not limited to, those suitable fororal administration, parenteral administration, including subcutaneous,intradermal, intramuscular, intravenous and intra-arterialadministration, as well as topical administration (e.g., administrationof an aerosolized formulation of respirable particles to the lungs of apatient afflicted with cystic fibrosis or lung cancer or a cream orlotion formulation for transdermal administration of patients withpsoriasis). The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart. The most suitable route of administration in any given case maydepend upon the subject, the nature and severity of the condition beingtreated, and the particular active compound, which is being used, aswould be readily determined by one of skill in the art.

Also provided herein are methods for the use of a compound describedherein having the characteristics set forth above for the preparation ofa medicament for upregulating or downregulating RNA expression in apatient having a disorder associated with aberrant or alternate splicingof a pre-mRNA molecule, as discussed above. In some embodiments, themedicament upregulates gene expression. In other embodiments, themedicament downregulates gene expression. In the manufacture of atmedicament according to the invention, the compound can be admixed with,inter alia, a pharmaceutically acceptable carrier. The carrier may be asolid or a liquid. One or more compounds may be incorporated in anycombination in the formulations described herein, which may be preparedby any of the well-known techniques of pharmacy, such as admixing thecomponents, and/or including one or more accessory therapeuticingredients.

The present inventors identify herein low molecular weight compounds(sometimes referred to herein as small molecules, which block mRNAsplicing and/or enhance (facilitate, augment) mRNA splicing. Thesplicing that can be regulated by the methods described herein includealternative splicing, e.g., exon skipping, intron retention, pseudoexonsskipping, exon exclusion, partial intron exclusion and others. Dependingon factors such as the splicing sequence and the RNA (or gene encodingthe RNA) or exon involved, modulation of splicing can be accomplished inthe presence of, or in the absence of, antisense oligonucleotides (AOs)that are specific for splicing sequences of interest. In someembodiments, a small molecule and an AO act synergistically.

In some aspects, a method comprises contacting a splice modulatingcompound (e.g., a SMSM) to a pre-mRNA that modulates splicing of thepre-mRNA to favor expression of a transcript that promotes cellproliferation. For example, an SMSM described herein can increase one ormore isoforms of a transcript that promotes cell proliferation. Forexample, an SMSM described herein can decrease expression one or moreisoforms of a transcript that prevents or inhibits cell proliferation.

In some aspects, a method comprises contacting a splice modulatingcompound (e.g., a SMSM) to a pre-mRNA that modulates splicing of thepre-mRNA to favor expression of a transcript that prevents or inhibitscell proliferation. For example, an SMSM described herein can increaseone or more isoforms of a transcript that prevents or inhibits cellproliferation. For example, an SMSM described herein can decreaseexpression one or more isoforms of a transcript that promotes cellproliferation.

In some embodiments, a method of modulating splicing of pre-mRNAcomprises using an SMSM to decrease expression or functionality of oneor more isoforms of a transcript in a subject. The method can compriseadministering an SMSM, or a composition comprising an SMSM, to asubject, wherein the SMSM binds to a pre-mRNA or a splicing complexcomponent and modulates splicing of the pre-mRNA to favor expression ofone or more isoforms of a transcript. The method can compriseadministering an SMSM, or a composition comprising an SMSM, to asubject, wherein the SMSM binds to a pre-mRNA or a splicing complexcomponent and modulates splicing of the pre-mRNA to disfavor expressionof one or more isoforms of a transcript.

In some embodiments, the present invention provides a method of treatinga subject afflicted with a disease or condition associated with aberrantsplicing of a pre-mRNA. The method can comprise administering an SMSM,or a composition comprising an SMSM, to a subject, wherein the SMSMbinds to a pre-mRNA or a splicing complex component and modulatessplicing of the pre-mRNA to inhibit expression of one or more isoformsof a transcript. The method can comprise administering an SMSM, or acomposition comprising an SMSM, to a subject, wherein the SMSM binds toa pre-mRNA or a splicing complex component and modulates the splicing ofthe pre-mRNA to increase expression of one or more isoforms of atranscript.

A number of diseases are associated with expression of an aberrant geneproduct (e.g., an RNA transcript or protein) of a gene. For example,aberrant amounts of a RNA transcript may lead to disease due tocorresponding changes in protein expression. Changes in the amount of aparticular RNA transcript may be the result of several factors. First,changes in the amount of RNA transcripts may be due to an aberrant levelof transcription of a particular gene, such as by the perturbation of atranscription factor or a portion of the transcription process,resulting in a change in the expression level of a particular RNAtranscript. Second, changes in the splicing of particular RNAtranscripts, such as by perturbation of a particular splicing process ormutations in the gene that lead to modified splicing can change thelevels of a particular RNA transcript. Changes to the stability of aparticular RNA transcript or to components that maintain RNA transcriptstability, such as the process of poly-A tail incorporation or an effecton certain factors or proteins that bind to and stabilize RNAtranscripts, may lead to changes in the levels of a particular RNAtranscript. The level of translation of particular RNA transcripts canalso affect the amount of those transcripts, affecting or upregulatingRNA transcript decay processes. Finally, aberrant RNA transport or RNAsequestration may also lead to changes in functional levels of RNAtranscripts, and may have an effect on the stability, furtherprocessing, or translation of the RNA transcripts.

In some embodiments, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts encoded by a pre-mRNA,comprising contacting a cell with an SMSM compound or a pharmaceuticallyacceptable salt thereof. In some embodiments, the cell is contacted withan SMSM compound or a pharmaceutically acceptable salt thereof in a cellculture. In other embodiments, the cell is contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof in a subject(e.g., a non-human animal subject or a human subject).

In some embodiments, provided herein are methods for treatment,prevention and/or delay of progression of a disease or conditioncomprising administering an effective amount of a small moleculesplicing modulator as described herein to a subject, in particular to amammal.

In some embodiments, provided herein are compositions and methods fortreating a disease or condition, including steric modulator compounds orpharmaceutically acceptable salts thereof that promote prevention orcorrection of exon skipping of a pre-mRNA. The invention furtherprovides compositions and methods for increasing production of maturemRNA and, in turn, protein, in cells of a subject in need thereof, forexample, a subject that can benefit from increased production ofprotein. The invention further provides compositions and methods fordecreasing production of mature mRNA and, in turn, protein, in cells ofa subject in need thereof, for example, a subject that can benefit fromdecreased production of protein. In one embodiment, the describedmethods may be used to treat subjects having a disease or conditioncaused by a mutation in a gene, including missense, splicing, frameshiftand nonsense mutations, as well as whole gene deletions, which result indeficient protein production. In another embodiment, the describedmethods may be used to treat subjects having a disease or condition notcaused by gene mutation. In some embodiments, the compositions andmethods of the present invention are used to treat subjects having adisease or condition, who can benefit from increased production ofprotein. In some embodiments, the compositions and methods of thepresent invention are used to treat subjects having a disease orcondition, who can benefit from increased production of protein. In someembodiments, the compositions and methods of the present invention areused to treat subjects having a disease or condition, who can benefitfrom decreased production of a protein.

In some embodiments, provided herein are methods of treating a diseaseor condition in a subject in need thereof by increasing the expressionof a target protein or functional RNA by cells of the subject, whereinthe cells have a mutation that causes, e.g., exon skipping or introninclusion, or a portion thereof, of pre-mRNA, wherein the pre-mRNAencodes the target protein or functional RNA. The method can comprisecontacting cells of a subject with an SMSM compound or apharmaceutically acceptable salt thereof that targets the pre-mRNAencoding the target protein or functional RNA or splicing complexcomponent, whereby splicing of an exon from a pre-mRNA encoding a targetprotein or functional RNA is prevented or inhibited, thereby increasinga level of mRNA encoding the target protein or functional RNA, andincreasing the expression of the target protein or functional RNA in thecells of the subject. In some embodiments, also disclosed herein is amethod of increasing expression of a target protein by cells having amutation or aberrant secondary or tertiary RNA structure that causesexon skipping of pre-mRNA, the pre-mRNA comprising a mutation oraberrant secondary or tertiary RNA structure that causes exon skipping.The method can comprise contacting the cells with an SMSM compound or apharmaceutically acceptable salt thereof that targets a pre-mRNAencoding a target protein or functional RNA, whereby splicing of an exonfrom a pre-mRNA encoding a target protein or functional RNA is preventedor inhibited, thereby increasing the level of mRNA encoding functionalprotein, and increasing the expression of protein in the cells. In someembodiments, the target protein is a tumor suppressor. In someembodiments, the target protein is a tumor promoter. In someembodiments, the target protein or the functional RNA is a compensatingprotein or a compensating functional RNA that functionally augments orreplaces a target protein or functional RNA that is deficient in amountor activity in the subject. In some embodiments, the cells are in orfrom a subject having a condition caused by a deficient amount oractivity of the protein. In some embodiments, the deficient amount ofthe target protein is caused by haploinsufficiency of the targetprotein, wherein the subject has a first allele encoding a functionaltarget protein, and a second allele from which the target protein is notproduced, or a second allele encoding a nonfunctional target protein,and wherein an SMSM compound or a pharmaceutically acceptable saltthereof binds to a targeted portion of a pre-mRNA transcribed from thefirst allele. In some embodiments, the target protein is produced in aform that is fully-functional compared to the equivalent proteinproduced from mRNA in which an exon has been skipped or is missing. Insome embodiments, the pre-mRNA is encoded by a genetic sequence with atleast about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequenceidentity to a pre-mRNA. In some embodiments, an SMSM compound or apharmaceutically acceptable salt thereof increases the amount of thetarget protein or the functional RNA by modulating alternative splicingof pre-mRNA transcribed from a gene encoding the functional RNA ortarget protein. In some embodiments, an SMSM compound or apharmaceutically acceptable salt thereof increases the amount of thetarget protein or the functional RNA by modulating aberrant splicingresulting from mutation of the gene encoding the target protein or thefunctional RNA.

In some embodiments, the total amount of the mRNA encoding the targetprotein or functional RNA produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is increased atleast about 10%, at least about 20%, at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90%, atleast about 100%, at least about 150%, at least about 200%, at leastabout 250%, at least about 300%,at least about 400%, or at least about500%, compared to the total amount of the mRNA encoding the targetprotein or functional RNA produced in a control cell.

In some embodiments, the total amount of the mRNA encoding the targetprotein or functional RNA produced in the cell contacted with than SMSMcompound or a pharmaceutically acceptable salt thereof is increasedabout 20% to about 300%, about 50% to about 300%, about 100% to about300%, about 150% to about 300%, about 20% to about 50%, about 20% toabout 100%, about 20% to about 150%, about 20% to about 200%, about 20%to about 250%, about 50% to about 100%, about 50% to about 150%, about50% to about 200%, about 50% to about 250%, about 100% to about 150%,about 100% to about 200%, about 100% to about 250%, about 150% to about200%, about 150% to about 250%, or about 200% to about 250%, compared tothe total amount of the mRNA encoding the target protein or functionalRNA produced in a control cell.

In some embodiments, the total amount of target protein produced by thecell contacted with an SMSMS compound or a pharmaceutically acceptablesalt thereof is increased at least about 20%, at least about 50%, atleast about 100%, at least about 150%, at least about 200%, at leastabout 250%, or at least about 300%, compared to the total amount oftarget protein produced by a control cell. In some embodiments, thetotal amount of target protein produced by the cell contacted with anSMSM compound or a pharmaceutically acceptable salt thereof is increasedabout 20% to about 300%, about 50% to about 300%, about 100% to about300%, about 150% to about 300%, about 20% to about 50%, about 20% toabout 100%, about 20% to about 150%, about 20% to about 200%, about 20%to about 250%, about 50% to about 100%, about 50% to about 150%, about50% to about 200%, about 50% to about 250%, about 100% to about 150%,about 100% to about 200%, about 100% to about 250%, about 150% to about200%, about 150% to about 250%, or about 200% to about 250%, compared tothe total amount of target protein produced by a control cell.

In some embodiments, a total amount of the mRNA encoding the targetprotein or functional RNA produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is increased atleast about 1.1-fold, at least about 1.5-fold, at least about 2-fold, atleast about 2.5-fold, at least about 3-fold, at least about 3.5-fold, atleast about 4-fold, at least about 5-fold, or at least about 10-foldcompared to the total amount of the mRNA encoding the target protein orfunctional RNA produced in a control cell. In some embodiments, a totalamount of an mRNA encoding the target protein or functional RNA producedin a cell contacted with an SMSM compound or a pharmaceuticallyacceptable salt thereof is increased about 1.1 to about 10-fold, about1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold,about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 toabout 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about4 to about 8-fold, or about 4 to about 9-fold, compared to a totalamount of the mRNA encoding the target protein or functional RNAproduced in a control cell.

In some embodiments, a total amount of target protein produced by a cellcontacted with an SMSM compound or a pharmaceutically acceptable saltthereof is increased at least about 1.1-fold, at least about 1.5-fold,at least about 2-fold, at least about 2.5-fold, at least about 3-fold,at least about 3.5-fold, at least about 4-fold, at least about 5-fold,or at least about 10-fold, compared to the total amount of targetprotein produced by a control cell. In some embodiments, the totalamount of target protein produced by the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is increasedabout 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold,about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 toabout 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about4 to about 7-fold, about 4 to about 8-fold, or about 4 to about 9-fold,compared to a total amount of target protein produced by a control cell.

In some embodiments, the total amount of the mRNA encoding the targetprotein or functional RNA produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is decreased atleast about 10%, at least about 20%, at least about 30%, at least about40%, at least about 50%, at least about 60%, at least about 70%, atleast about 80%, at least about 90%, or at least about 100%, compared tothe total amount of the mRNA encoding the target protein or functionalRNA produced in a control cell.

In some embodiments, the total amount of the mRNA encoding the targetprotein or functional RNA produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is decreasedabout 10% to about 100%, about 20% to about 100%, about 30% to about100%, about 40% to about 100%, about 50% to about 100%, about 60% toabout 100%, about 70% to about 100%, about 80% to about 100% about 90%to about 100%, about 20% to about 30%, about 20% to about 40%, about 20%to about 50%, about 20% to about 60%, about 20% to about 70%, about 20%to about 80%, about 20% to about 90%, about 30% to about 40%, about 30%to about 50%, about 30% to about 60%, about 30% to about 70%, about 30%to about 80%, about 30% to about 90%, about 40% to about 50%, about 40%to about 60%, about 40% to about 70%, about 40% to about 80%, about 40%to about 90%, about 50% to about 60%, about 50% to about 70%, about 50%to about 80%, about 50% to about 90%, about 60% to about 70%, about 60%to about 80%, about 60% to about 90%, 70% to about 80%, about 70% toabout 90%, or about 80% to about 90%, compared to the total amount ofthe mRNA encoding the target protein or functional RNA produced in acontrol cell.

In some embodiments, the total amount of target protein produced by thecell contacted with an SMSM compound or a pharmaceutically acceptablesalt thereof is decreased at least about 10%, at least about 20%, atleast about 30%, at least about 40%, at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90%, or atleast about 100%, compared to the total amount of target proteinproduced by a control cell. In some embodiments, the total amount oftarget protein produced by the cell contacted with an SMSM compound or apharmaceutically acceptable salt thereof is decreased about 10% to about100%, about 20% to about 100%, about 30% to about 100%, about 40% toabout 100%, about 50% to about 100%, about 60% to about 100%, about 70%to about 100%, about 80% to about 100% about 90% to about 100%, about20% to about 30%, about 20% to about 40%, about 20% to about 50%, about20% to about 60%, about 20% to about 70%, about 20% to about 80%, about20% to about 90%, about 30% to about 40%, about 30% to about 50%, about30% to about 60%, about 30% to about 70%, about 30% to about 80%, about30% to about 90%, about 40% to about 50%, about 40% to about 60%, about40% to about 70%, about 40% to about 80%, about 40% to about 90%, about50% to about 60%, about 50% to about 70%, about 50% to about 80%, about50% to about 90%, about 60% to about 70%, about 60% to about 80%, about60% to about 90%, 70% to about 80%, about 70% to about 90%, or about 80%to about 90%, compared to the total amount of target protein produced bya control cell.

In some embodiments, the difference in amount between a first splicevariant and a second splice variant encoding a target protein orfunctional RNA isoform produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is increasedabout 20% to about 300%, about 50% to about 300%, about 100% to about300%, about 150% to about 300%, about 20% to about 50%, about 20% toabout 100%, about 20% to about 150%, about 20% to about 200%, about 20%to about 250%, about 50% to about 100%, about 50% to about 150%, about50% to about 200%, about 50% to about 250%, about 100% to about 150%,about 100% to about 200%, about 100% to about 250%, about 150% to about200%, about 150% to about 250%, about 200% to about 250%, at least about20%, at least about 50%, at least about 100%, at least about 150%, atleast about 200%, at least about 250%, or at least about 300%, comparedto the difference in amounts between the two splice variants produced bya control cell. In some embodiments, the difference in amount between afirst protein isoform expressed from a first splice variant and a secondprotein isoform expressed from a second splice variant produced by thecell contacted with an SMSM compound or a pharmaceutically acceptablesalt thereof is increased about 20% to about 300%, about 50% to about300%, about 100% to about 300%, about 150% to about 300%, about 20% toabout 50%, about 20% to about 100%, about 20% to about 150%, about 20%to about 200%, about 20% to about 250%, about 50% to about 100%, about50% to about 150%, about 50% to about 200%, about 50% to about 250%,about 100% to about 150%, about 100% to about 200%, about 100% to about250%, about 150% to about 200%, about 150% to about 250%, about 200% toabout 250%, at least about 20%, at least about 50%, at least about 100%,at least about 150%, at least about 200%, at least about 250%, or atleast about 300%, compared to the difference in amounts between twoprotein isoforms produced from the splice variants produced by a controlcell.

In some embodiments, the difference in amount between a first splicevariant and a second splice variant encoding a target protein orfunctional RNA isoform produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is increasedabout 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold,about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 toabout 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, atleast about 1.1-fold, at least about 1.5-fold, at least about 2-fold, atleast about 2.5-fold, at least about 3-fold, at least about 3.5-fold, atleast about 4-fold, at least about 5-fold, or at least about 10-fold,compared to the difference in amounts between the two splice variantsproduced by a control cell. In some embodiments, the difference inamount between a first protein isoform expressed from a first splicevariant and a second protein isoform expressed from a second splicevariant produced by the cell contacted with an SMSM compound or apharmaceutically acceptable salt thereof is increased about 1.1 to about10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold,about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 toabout 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold,about 4 to about 8-fold, about 4 to about 9-fold, at least about1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about4-fold, at least about 5-fold, or at least about 10-fold, compared tothe difference in amounts between two protein isoforms expressed fromthe splice variants produced by a control cell.

In some embodiments, a difference in amount between a first splicevariant and a second splice variant encoding a target protein orfunctional RNA isoform produced in a cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is decreasedabout 20% to about 300%, about 50% to about 300%, about 100% to about300%, about 150% to about 300%, about 20% to about 50%, about 20% toabout 100%, about 20% to about 150%, about 20% to about 200%, about 20%to about 250%, about 50% to about 100%, about 50% to about 150%, about50% to about 200%, about 50% to about 250%, about 100% to about 150%,about 100% to about 200%, about 100% to about 250%, about 150% to about200%, about 150% to about 250%, about 200% to about 250%, at least about20%, at least about 50%, at least about 100%, at least about 150%, atleast about 200%, at least about 250%, or at least about 300%, comparedto the difference in amounts between the two splice variants produced bya control cell. In some embodiments, a difference in amount between afirst protein isoform expressed from a first splice variant and a secondprotein isoform expressed from a second splice variant produced by acell contacted with an SMSM compound or a pharmaceutically acceptablesalt thereof is decreased about 20% to about 300%, about 50% to about300%, about 100% to about 300%, about 150% to about 300%, about 20% toabout 50%, about 20% to about 100%, about 20% to about 150%, about 20%to about 200%, about 20% to about 250%, about 50% to about 100%, about50% to about 150%, about 50% to about 200%, about 50% to about 250%,about 100% to about 150%, about 100% to about 200%, about 100% to about250%, about 150% to about 200%, about 150% to about 250%, about 200% toabout 250%, at least about 20%, at least about 50%, at least about 100%,at least about 150%, at least about 200%, at least about 250%, or atleast about 300%, compared to a difference in amounts between twoprotein isoforms produced from the splice variants produced by a controlcell.

In some embodiments, the difference in amount between a first splicevariant and a second splice variant encoding a target protein orfunctional RNA isoform produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is decreasedabout 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold,about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 toabout 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, atleast about 1.1-fold, at least about 1.5-fold, at least about 2-fold, atleast about 2.5-fold, at least about 3-fold, at least about 3.5-fold, atleast about 4-fold, at least about 5-fold, or at least about 10-fold,compared to the difference in amounts between the two splice variantsproduced by a control cell. In some embodiments, the difference inamount between a first protein isoform expressed from a first splicevariant and a second protein isoform expressed from a second splicevariant produced by the cell contacted with an SMSM compound or apharmaceutically acceptable salt thereof is decreased about 1.1 to about10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold,about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 toabout 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold,about 4 to about 8-fold, about 4 to about 9-fold, at least about1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about4-fold, at least about 5-fold, or at least about 10-fold, compared tothe difference in amounts between two protein isoforms express from thesplice variants produced by a control cell.

The ratio of a first isoform and a second isoform may contribute to anumber of conditions or diseases. In some embodiments, a subject withouta condition or disease has a first isoform to second isoform ratio of1:1. In some embodiments, a subject with a condition or diseasedescribed herein has a first isoform to second isoform ratio of about1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.In some embodiments, a subject with a condition or disease describedherein has a first isoform to second isoform ratio from about 1:1 toabout 1:1.1, about 1:1 to about 1:1.2, about 1:1 to about 1:1.3, about1:1 to about 1:1.4, about 1:1 to about 1:1.5, about 1:1 to about 1:1.6,about 1:1 to about 1:1.8, about 1:1 to about 1:2, about 1:1 to about1:3, about 1:1 to about 1:3.5, about 1:1 to about 1:4, about 1:1 toabout 1:4.5, about 1:1 to about 1:5, 1:2 to about 1:3, about 1:2 toabout 1:4, about 1:2 to about 1:5, about 1:3 to about 1:4, about 1:3 toabout 1:5, or about 1:4 to about 1:5.

In some embodiments, binding of an SMSM compound or a pharmaceuticallyacceptable salt thereof to pre-mRNA prevents splicing out of one or moreexons and/or introns and/or proteins thereof, from the population ofpre-mRNAs to produce mRNA encoding the target protein or functional RNA.In some embodiments, the cell comprises a population of pre-mRNAstranscribed from the gene encoding the target protein or functional RNA,wherein the population of pre-mRNAs comprises a mutation that causes thesplicing out of one or more exons, and wherein an SMSM compound or apharmaceutically acceptable salt thereof binds to the mutation thatcauses the splicing out of the one or more exons in the population ofpre-mRNAs. In some embodiments, the binding of an SMSM compound or apharmaceutically acceptable salt thereof to the mutation that causes thesplicing out of the one or more exons prevents splicing out of the oneor more exons from the population of pre-mRNAs to produce mRNA encodingthe target protein or functional RNA. In some embodiments, the conditionis a disease or disorder. In some embodiments, the method furthercomprises assessing protein expression. In some embodiments, an SMSMcompound or a pharmaceutically acceptable salt thereof binds to atargeted portion of a pre-mRNA.

In some embodiments, the binding of an SMSM compound or apharmaceutically acceptable salt thereof catalyzes the inclusion of amissing exon or removal of an undesired retained intron or portionsthereof, resulting in healthy mRNA and proteins. In some embodiments,the binding of an SMSM compound or a pharmaceutically acceptable saltthereof has minimal to no effect on non-diseased cells.

In some embodiments, an SMSM kills cells at an IC₅₀ of less than 50 nM.In some embodiments, the cells are primary cells. In some embodiments,an SMSM kills the cells at an IC₅₀ of less than 48 nM, 45 nM, 40 nM, 35nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM, 5 nM, 3 nM, or 1 nM.

In some embodiments, an SMSM modulates splicing at a splice sitesequence of a polynucleotide of the primary cells. In some embodiments,an SMSM modulates proliferation or survival of the primary cells. Insome embodiments, the primary cells are primary diseased cells. In someembodiments, the primary diseased cells are primary cancer cells. Insome embodiments, the SMSM is present at a concentration of at leastabout 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 100 μM, 1 mM, 10 mM, 100 mM, or1 M. In some embodiments, at least about 5%, 10%, 25%, 30%, 40%, 50%,60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% of the primarydiseased cells are killed. In some embodiments, at least about 5%, 10%,25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or100% of the primary diseased cells undergo apoptosis. In someembodiments, at least about 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 75%,80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% of the primary diseased cellsundergo necrosis. In some embodiments, proliferation is reduced orinhibited in at least about 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 75%,80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% of the primary diseased cells.In some embodiments, the primary diseased cells are non-transformedcells.

In some embodiments, an SMSM reduces a size of a tumor in a subject. Insome embodiments, a size of a tumor in a subject administered an SMSM ora pharmaceutically acceptable salt thereof is reduced by at least about1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%,80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% in the subject. In someembodiments, a diameter of a tumor in a subject administered an SMSM ora pharmaceutically acceptable salt thereof is reduced by at least about1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%,80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, a volumeof the tumor is reduced by at least about 1%, 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%,97%, 98%, or 99% in the subject. In some embodiments, the tumor ismalignant.

In some embodiments, a method comprises contacting an SMSM to primarynon-diseased cells. In some embodiments, at most about 1%, 5%, 10%, 15%,20%, 25%, or 50% of the primary non-diseased cells are killed. In someembodiments, at most about 1%, 5%, 10%, 15%, 20%, 25%, or 50% of theprimary non-diseased cells undergo apoptosis. In some embodiments, atmost about 1%, 5%, 10%, 15%, 20%, 25%, or 50% of the primarynon-diseased cells undergo necrosis. In some embodiments, proliferationis reduced or inhibited in at most about 1%, 5%, 10%, 15%, 20%, 25%, or50% of the primary non-diseased cells. In some embodiments, the primarynon-diseased cells are of the same tissue as the primary diseased cells.In some embodiments, the primary non-diseased cells are differentiatedcells.

An SMSM can modulate splicing at a splice site of a polynucleotide anddoes not exhibit significant toxicity. In some embodiments, an SMSMpenetrates the blood brain barrier (BBB) when administered to a subject.

In some embodiments, an SMSM has a brain/blood AUC of at least about0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 40, or higher.

In some embodiments, an SMSM provided herein, e.g., an SMSM of Formula(I)-(IV), has an apparent permeability (P_(app)) of at least about 1, atleast about 2, at least about 3, at least about 4, at least about 5, atleast about 10, at least about 15, at least about 20, at least about 30,at least about 40, at least about 50, at least about 60, at least about70, at least about 80, at least about 90, or at least about 100, asdetermined by MDCK-MDR1 Permeability assay. In some embodiments, an SMSMprovided herein has an apparent permeability of at least about 10, atleast about 20, or at least about 50.

In some embodiments, an SMSM provided herein, e.g., an SMSM of Formula(I)-(IV), has an Efflux Ratio (ER) of at most about 3. In someembodiments, an SMSM provided herein has an Efflux ratio within a rangeof from about 1, about 2, about 3 or about 4, to about 5, about 6, about7, about 8, about 9, about 10, about 12 about 15, or about 20, asdetermined by MDCK-MDR1 Permeability assay. In some embodiments, an SMSMprovided herein has an Efflux ratio of from about 3 to about 10. In someembodiments, an SMSM provided herein has an Efflux ratio that is at mostabout 3, at most about 2, or at most about 1. In some embodiments, anSMSM provided herein has an Efflux ratio of larger than about 10. Insome embodiments, an SMSM provided herein has an Efflux ratio of atleast about 10, at least about 20, at least about 50, at least about100, at least about 200, or at least about 300.

In some embodiments, an SMSM has a half-life of at least about 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160,170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375,400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or1000 hours in a human.

In some embodiments, an SMSM is stable at room temperature for at least1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23 or 24 hours; or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 months; or at least 1, 2, 3, 4, or 5 years. In some embodiments,an SMSM is stable at 4° C. for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours; or forat least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months; or at least 1,2, 3, 4, or 5 years. In some embodiments, an SMSM is stable at roomtemperature in water or an organic solvent for at least 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24hours; or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months; orat least 1, 2, 3, 4, or 5 years. In some embodiments, an SMSM is stableat 4° C. in water or an organic solvent for at least 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24hours; or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months;or at least 1, 2, 3, 4, or 5 years.

In some embodiments, an SMSM has an cell viability IC₅₀ of 0.01-10 nM,0.01-5 nM, 0.01-2.5 nM, 0.01-1 nM, 0.01-0.75 nM, 0.01-0.5 nM, 0.01-0.25nM, 0.01-0.1 nM, 0.1-100 nM, 0.1-50 nM, 0.1-25 nM, 0.1-10 nM, 0.1-7.5nM, 0.1-5 nM, 0.1-2.5 nM, 2-1000 nM, 2-500 nM, 2-250 nM, 2-100 nM, 2-75nM, 2-50 nM, 2-25 nM, 2-10 nM, 10-1000 nM, 10-500 nM, 10-250 nM, 10-100nM, 10-75 nM, 10-50 nM, 10-25 nM, 25-1000 nM, 25-500 nM, 25-250 nM,25-100 nM, 25-75 nM, 25-50 nM, 50-1000 nM, 50-500 nM, 50-250 nM, 50-100nM, 50-75 nM, 60-70 nM, 100-1000 nM, 100-500 nM, 100-250 nM, 250-1000nM, 250-500 nM, or 500-1000 nM.

In some embodiments, an SMSM has an cell viability IC₅₀ of at most 2 nM,3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21 nM, 22 nM, 23 nM, 24nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, 50 nM, 51 nM, 52 nM, 53 nM, 54nM, 55 nM, 56 nM, 57 nM, 58 nM, 59 nM, 60 nM, 61 nM, 62 nM, 63 nM, 64nM, 65 nM, 66 nM, 67 nM, 68 nM, 69 nM, 70 nM, 71 nM, 72 nM, 73 nM, 74nM, 75 nM, 76 nM, 77 nM, 78 nM, 79 nM, 80 nM, 81 nM, 82 nM, 83 nM, 84nM, 85 nM, 90 nM, 95 nM, 100 nM, 110 nM, 120 nM, 130 nM, 140 nM, 150 nM,160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM, 220 nM, 230 nM, 240 nM,250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM,475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM,900 nM, 950 nM, 1 μM, or 10 μM.

In some embodiments, an SMSM reduces cell proliferation of diseasedcells by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%,35%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%,61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% when thecells are treated with the SMSM at a concentration of 2-1000 nM, 2-500nM, 2-250 nM, 2-100 nM, 2-75 nM, 2-50 nM, 2-25 nM, 2-10 nM, 10-1000 nM,10-500 nM, 10-250 nM, 10-100 nM, 10-75 nM, 10-50 nM, 10-25 nM, 25-1000nM, 25-500 nM, 25-250 nM, 25-100 nM, 25-75 nM, 25-50 nM, 50-1000 nM,50-500 nM, 50-250 nM, 50-100 nM, 50-75 nM, 60-70 nM, 100-1000 nM,100-500 nM, 100-250 nM, 250-1000 nM, 250-500 nM, or 500-1000 nM for atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 21, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 hours.

In some embodiments, an SMSM reduces cell proliferation of diseasedcells by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%,35%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%,61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% when thecells are treated with the SMSM at a concentration of at least 2 nM, 3nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21 nM, 22 nM, 23 nM, 24nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, 50 nM, 51 nM, 52 nM, 53 nM, 54nM, 55 nM, 56 nM, 57 nM, 58 nM, 59 nM, 60 nM, 61 nM, 62 nM, 63 nM, 64nM, 65 nM, 66 nM, 67 nM, 68 nM, 69 nM, 70 nM, 71 nM, 72 nM, 73 nM, 74nM, 75 nM, 76 nM, 77 nM, 78 nM, 79 nM, 80 nM, 81 nM, 82 nM, 83 nM, 84nM, 85 nM, 90 nM, 95 nM, 100 nM, 110 nM, 120 nM, 130 nM, 140 nM, 150 nM,160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM, 220 nM, 230 nM, 240 nM,250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM,475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM,900 nM, 950 nM, 1 μM, or 10 μM for at least 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 21, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, or 48 hours.

In some embodiments, an SMSM reduces viability of diseased cells by morethan 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, or 100%. when the cells are treated with the SMSM at aconcentration of 2-1000 nM, 2-500 nM, 2-250 nM, 2-100 nM, 2-75 nM, 2-50nM, 2-25 nM, 2-10 nM, 10-1000 nM, 10-500 nM, 10-250 nM, 10-100 nM, 10-75nM, 10-50 nM, 10-25 nM, 25-1000 nM, 25-500 nM, 25-250 nM, 25-100 nM,25-75 nM, 25-50 nM, 50-1000 nM, 50-500 nM, 50-250 nM, 50-100 nM, 50-75nM, 60-70 nM, 100-1000 nM, 100-500 nM, 100-250 nM, 250-1000 nM, 250-500nM, or 500-1000 nM for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,21, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or48 hours.

In some embodiments, an SMSM reduces viability of diseased cells by morethan 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, or 100% when the cells are treated with the SMSM at a concentrationof at least 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21nM, 22 nM, 23 nM, 24 nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, 50 nM, 51nM, 52 nM, 53 nM, 54 nM, 55 nM, 56 nM, 57 nM, 58 nM, 59 nM, 60 nM, 61nM, 62 nM, 63 nM, 64 nM, 65 nM, 66 nM, 67 nM, 68 nM, 69 nM, 70 nM, 71nM, 72 nM, 73 nM, 74 nM, 75 nM, 76 nM, 77 nM, 78 nM, 79 nM, 80 nM, 81nM, 82 nM, 83 nM, 84 nM, 85 nM, 90 nM, 95 nM, 100 nM, 110 nM, 120 nM,130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM,220 nM, 230 nM, 240 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM,400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM,750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 μM, or 10 μM for at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 21, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, or 48 hours.

In some embodiments, an SMSM does not reduce viability of non-diseasedcells by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%,35%, 40%, 45%, or 50 when the cells are treated with the SMSM at aconcentration of 2-1000 nM, 2-500 nM, 2-250 nM, 2-100 nM, 2-75 nM, 2-50nM, 2-25 nM, 2-10 nM, 10-1000 nM, 10-500 nM, 10-250 nM, 10-100 nM, 10-75nM, 10-50 nM, 10-25 nM, 25-1000 nM, 25-500 nM, 25-250 nM, 25-100 nM,25-75 nM, 25-50 nM, 50-1000 nM, 50-500 nM, 50-250 nM, 50-100 nM, 50-75nM, 60-70 nM, 100-1000 nM, 100-500 nM, 100-250 nM, 250-1000 nM, 250-500nM, or 500-1000 nM for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,21, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or48 hours.

In some embodiments, an SMSM does not reduce viability of non-diseasedcells by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%,35%, 40%, 45%, or 50% when the cells are treated with the SMSM at aconcentration of at least 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19nM, 20 nM, 21 nM, 22 nM, 23 nM, 24 nM, 25 nM, 30 nM, 35 nM, 40 nM, 45nM, 50 nM, 51 nM, 52 nM, 53 nM, 54 nM, 55 nM, 56 nM, 57 nM, 58 nM, 59nM, 60 nM, 61 nM, 62 nM, 63 nM, 64 nM, 65 nM, 66 nM, 67 nM, 68 nM, 69nM, 70 nM, 71 nM, 72 nM, 73 nM, 74 nM, 75 nM, 76 nM, 77 nM, 78 nM, 79nM, 80 nM, 81 nM, 82 nM, 83 nM, 84 nM, 85 nM, 90 nM, 95 nM, 100 nM, 110nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200nM, 210 nM, 220 nM, 230 nM, 240 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 μM, or 10 μM forat least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 21, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 hours.

In some embodiments, an SMSM reduces a size of a tumor in a subject byat least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%,18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 51%,52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%,66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%,80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99%, or 100%.

In some embodiments, an SMSM inhibits tumor growth of a tumor in asubject by at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%,50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%,64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%,78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

SMSM Targets

Aberrant splicing of mRNA, such as pre-mRNA, can result in a defectiveprotein and can cause a disease or a disorder in a subject. Thecompositions and methods described herein can reduce this aberrantsplicing of mRNA, such as pre-mRNA, and treat a disease or a disordercaused by this aberrant splicing.

Diseases associated with changes to RNA transcript amount are oftentreated with a focus on the aberrant protein expression. However, if theprocesses responsible for the aberrant changes in RNA levels, such ascomponents of the splicing process or associated transcription factorsor associated stability factors, could be targeted by treatment with asmall molecule, it would be possible to restore protein expressionlevels such that the unwanted effects of the expression of aberrantlevels of RNA transcripts or associated proteins. Therefore, there is aneed for methods of modulating the amount of RNA transcripts encoded bycertain genes as a way to prevent or treat diseases associated withaberrant expression of the RNA transcripts or associated proteins.

Structural Targets

Mutations and/or aberrant secondary or tertiary RNA structures incis-acting elements can induce three-dimensional structural change inpre-mRNA. Mutations and/or aberrant secondary RNA structures incis-acting elements can induce three-dimensional structural change inpre-mRNA when the pre-mRNA is, for example, bound to at least one snRNA,or at least one snRNP, or at least one other auxiliary splicing factor.For example, non-canonical base pairing of a non-canonical splice sitesequence to a snRNA can form a bulge. For example, a bulge can be formedwhen the 5′ss is bound to U1-U12 snRNA or a portion thereof. Forexample, a bulge can be induced to form when 5′ss containing at leastone mutation is bound to U1-U12 snRNA or a portion thereof. For example,a bulge can be formed when the cryptic 5′ss is bound to U1-U12 snRNA ora portion thereof. For example, a bulge can be induced to form whencryptic 5′ss containing at least one mutation is bound to U1-U12 snRNAor a portion thereof. For example, a bulge can be formed when the 3′ssis bound to U2 snRNA or a portion thereof. For example, a bulge can beinduced to form when the 3′ss is bound to U2 snRNA or a portion thereof.For example, a bulge can be formed when the cryptic 3′ss is bound to U2snRNA or a portion thereof. For example, a bulge can be induced to formwhen the cryptic 3′ss is bound to U2 snRNA or a portion thereof. Theprotein components of UI and U2 may or may not present to form thebulge. Exemplary 5′ splice site mutations and/or with aberrant secondaryand/or tertiary structures that can induce a bulge structure aredescribed herein. A polynucleotide in the methods disclosed herein cancontain any one of exemplary the 5′ splice site sequences describedherein.

In some embodiments, a small molecule can bind to a bulge. In someembodiments, a bulge is naturally occurring. In some embodiments, abulge is formed by non-canonical base-pairing between the splice siteand the small nuclear RNA. For example, a bulge can be formed bynon-canonical base-pairing between the 5′ss and U1-U12 snRNA. The bulgecan comprise 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides,5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13nucleotides, 14 nucleotides, or 15 nucleotides. In some embodiments,3-dimensional structural changes can be induced by a mutation withoutbulge formation. In some embodiments, a bulge may be formed without anymutation in a splice site. In some embodiments, a recognition portioncan be formed by a mutation in any of the cis-acting elements. In someembodiments, a small molecule can bind to a recognition portion that isinduced by a mutation. In some embodiments, a mutation and/or aberrantsecondary or tertiary RNA structure at an authentic 5′ splice site canresult in splicing at a cryptic 5′ splice site. In some embodiments, amutation and/or aberrant secondary or tertiary RNA structure can be inone of the regulatory elements including ESEs, ESSs, ISEs, and ISSs.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide in an exon. In someembodiments, a target of an SMSM is a pre-mRNA comprising a splice sitesequence with a bulged nucleotide upstream (5′) of the splice site ofthe splice site sequence. In some embodiments, a target of an SMSM is apre-mRNA comprising a splice site sequence with a bulged nucleotide atthe −1 position relative to the splice site of the splice site sequence.For example, a target of an SMSM can be a pre-mRNA comprising a splicesite sequence of NNN*nnnnnn, wherein N* represents a bulged nucleotide.In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide at the −2 positionrelative to the splice site of the splice site sequence. For example, atarget of an SMSM can be a pre-mRNA comprising a splice site sequence ofNN*Nnnnnnn, wherein N* represents a bulged nucleotide. In someembodiments, a target of an SMSM is a pre-mRNA comprising a splice sitesequence with a bulged nucleotide at the −3 position relative to thesplice site of the splice site sequence. For example, a target of anSMSM can be a pre-mRNA comprising a splice site sequence of N*NNnnnnnn,wherein N* represents a bulged nucleotide.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide in an intron. In someembodiments, a target of an SMSM is a pre-mRNA comprising a splice sitesequence with a bulged nucleotide downstream (3′) of the splice site ofthe splice site sequence.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide at the +1 positionrelative to the splice site of the splice site sequence. For example, atarget of an SMSM can be a pre-mRNA comprising a splice site sequence ofNNNn*nnnnn, wherein n* represents a bulged nucleotide. In someembodiments, a target of an SMSM is a pre-mRNA comprising a splice sitesequence with a bulged nucleotide at the +2 position relative to thesplice site of the splice site sequence. For example, a target of anSMSM can be a pre-mRNA comprising a splice site sequence of NNNnn*nnnn,wherein n* represents a bulged nucleotide. In some embodiments, a targetof an SMSM is a pre-mRNA comprising a splice site sequence with a bulgednucleotide at the +3 position relative to the splice site of the splicesite sequence. For example, a target of an SMSM can be a pre-mRNAcomprising a splice site sequence of NNNnnn*nnn, wherein n* represents abulged nucleotide. In some embodiments, a target of an SMSM is apre-mRNA comprising a splice site sequence with a bulged nucleotide atthe +4 position relative to the splice site of the splice site sequence.For example, a target of an SMSM can be a pre-mRNA comprising a splicesite sequence of NNNnnnn*nn, wherein n* represents a bulged nucleotide.In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide at the +5 positionrelative to the splice site of the splice site sequence. For example, atarget of an SMSM can be a pre-mRNA comprising a splice site sequence ofNNNnnnnn*n, wherein n* represents a bulged nucleotide. In someembodiments, a target of an SMSM is a pre-mRNA comprising a splice sitesequence with a bulged nucleotide at the +6 position relative to thesplice site of the splice site sequence. For example, a target of anSMSM can be a pre-mRNA comprising a splice site sequence of NNNnnnnnn*,wherein n* represents a bulged nucleotide. In some embodiments, a targetof an SMSM is a pre-mRNA comprising a splice site sequence with a bulgednucleotide at the +7 position relative to the splice site of the splicesite sequence. For example, a target of an SMSM can be a pre-mRNAcomprising a splice site sequence of NNNnnnnnnn*, wherein n* representsa bulged nucleotide.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with one or more bulged nucleotides at the −1, −2,−3, +1, +2, +3, +4, +5, +6 and/or +7 position relative to the splicesite of the splice site sequence. For example, a target of an SMSM canbe a pre-mRNA comprising a splice site sequence of NNN*nnnnnn,NN*Nnnnnnn, N*NNnnnnnn, NNNn*nnnnn, NNNnn*nnnn, NNNnnn*nnn, NNNnnnn*nn,NNNnnnnn*n, NNNnnnnnn*, or NNNnnnnnnn*, wherein N* or n* represents abulged nucleotide.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with one or more bulged nucleotides at the −1, −2,and/or −3 position relative to the splice site of the splice sitesequence. For example, a target of an SMSM can be a pre-mRNA comprisinga splice site sequence of NNN*nnnnnn, NN*Nnnnnnn, or N*NNnnnnnn, whereinN* represents a bulged nucleotide.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with one or more bulged nucleotides at the +1, +2,+3, +4, +5, +6 and/or +7 position relative to the splice site of thesplice site sequence. For example, a target of an SMSM can be a pre-mRNAcomprising a splice site sequence of NNNn*nnnnn, NNNnn*nnnn, NNNnnn*nnn,NNNnnnn*nn, NNNnnnnn*n, NNNnnnnnn*, or NNNnnnnnnn*, wherein n*represents a bulged nucleotide.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide at the −1 positionrelative to the splice site of the splice site sequence and a bulgednucleotide at the −2 position relative to the splice site of the splicesite sequence. For example, a target of an SMSM can be a pre-mRNAcomprising a splice site sequence of NN*N*nnnnnn, wherein N* representsa bulged nucleotide. In some embodiments, a target of an SMSM is apre-mRNA comprising a splice site sequence with a bulged nucleotide atthe −2 position relative to the splice site of the splice site sequenceand a bulged nucleotide at the −3 position relative to the splice siteof the splice site sequence. For example, a target of an SMSM can be apre-mRNA comprising a splice site sequence of N*N*Nnnnnnn, wherein N*represents a bulged nucleotide.

In some embodiments, an SMSM interacts with a bulged nucleotide of anRNA duplex comprising a splice site. In some embodiments, the RNA duplexcomprises pre-mRNA. In some embodiments, an SMSM binds to an RNA duplexand interacts with an unpaired bulged nucleobase of an RNA duplexcomprising a splice site. In some embodiments, a first portion of theSMSM interacts with the bulged nucleotide on a first RNA strand of theRNA duplex. In some embodiments, a second portion of the SMSM interactswith one or more nucleotides of a second RNA strand of the RNA duplex,wherein the first RNA strand is not the second RNA strand. In someembodiments, the SMSM forms one or more intermolecular interactions withthe duplex RNA, for example, an ionic interaction, a hydrogen bond, adipole-dipole interaction or a van der Waals interaction. In someembodiments, the SMSM forms one or more intermolecular interactions withthe bulged nucleotide, for example, an ionic interaction, a hydrogenbond, a dipole-dipole interaction or a van der Waals interaction.

In some embodiments, the duplex RNA comprises an alpha helix. In someembodiments, the bulged nucleotide is located on an external portion ofa helix of the duplex RNA. In some embodiments, the bulged nucleotide islocated within an internal portion of the helix of the duplex RNA.

In some embodiments, a rate of exchange of the bulged nucleotide fromwithin the interior of a helix of the duplex RNA to an exterior portionof the helix is reduced.

In some embodiments, the SMSM modulates a distance of the bulgednucleotide from a second nucleotide of the duplex RNA. In someembodiments, the SMSM reduces the distance of the bulged nucleotide froma second nucleotide of the duplex RNA. In some embodiments, the SMSMincreases the distance of the bulged nucleotide from a second nucleotideof the duplex RNA.

In some embodiments, the bulged nucleotide is located within theinterior of a helix of the duplex RNA of the complex. In someembodiments, the bulged nucleotide has modulated base stacking within anRNA strand of the RNA duplex. In some embodiments, the bulged nucleotidehas increased base stacking within an RNA strand of the RNA duplex. Insome embodiments, the bulged nucleotide has decreased base stackingwithin an RNA strand of the RNA duplex.

In some embodiments, the SMSM modulates splicing at the splice site ofthe RNA duplex. In some embodiments, the SMSM increases splicing at thesplice site of the RNA duplex. In some embodiments, the SMSM reducessplicing at the splice site of the RNA duplex. In some embodiments, theSMSM reduces a size of a bulge of the RNA duplex. In some embodiments,the SMSM removes a bulge of the RNA duplex. In some embodiments, theSMSM stabilizes a bulge of the RNA duplex.

In some embodiments, the unpaired bulged nucleotide is free to rotatearound a phosphate backbone of an RNA strand of the RNA duplex in theabsence of the SMSM. In some embodiments, the SMSM reduces a rate ofrotation of the unpaired bulged nucleotide. In some embodiments, theSMSM reduces a rate of rotation of the unpaired bulged nucleotide arounda phosphate backbone of an RNA strand of the RNA duplex.

In some embodiments, the SMSM is not an aptamer.

Also, provided herein is a method of modulating splicing comprisingcontacting a small molecule splicing modulator compound (SMSM) to acell; wherein the SMSM interacts with an unpaired bulged nucleotide ofan RNA duplex in the cell; wherein the duplex RNA comprises a splicesite; and wherein the SMSM modulates splicing of the RNA duplex.

Provided herein is a method for modulating the relative position of afirst nucleotide relative to a second nucleotide, wherein the firstnucleotide and the second nucleotide are within a duplex RNA, the methodcomprising contacting a small molecule splicing modulator compound(SMSM) to the duplex RNA, or a pharmaceutically acceptable salt thereof,wherein the first nucleotide is a bulged nucleotide of the RNA duplex;wherein the duplex RNA comprises a splice site.

In some embodiments, the duplex RNA comprises a helix.

In some embodiments, the bulged nucleotide is located on an externalportion of a helix of the duplex RNA prior to contacting the SMSM.

In some embodiments, SMSM forms one or more intermolecular interactionswith the duplex RNA.

In some embodiments, the SMSM forms one or more intermolecularinteractions with an unpaired bulged nucleotide. In some embodiments,the intermolecular interaction is selected from the group comprising anionic interaction, a hydrogen bond, a dipole-dipole interaction or a vander Waals interaction. In some embodiments, a rate of exchange of theunpaired bulged nucleotide from within the interior of a helix of theduplex RNA to an exterior portion of the helix is reduced. In someembodiments, a rate of rotation of the unpaired bulged nucleotide isreduced. In some embodiments, a rate of rotation of the unpaired bulgednucleotide around a phosphate backbone of an RNA strand of the RNAduplex is reduced. In some embodiments, a distance of the unpairedbulged nucleotide from a second nucleotide of the duplex RNA ismodulated after contacting the SMSM. In some embodiments, the distanceof the unpaired bulged nucleotide from a second nucleotide of the duplexRNA is reduced. In some embodiments, unpaired bulged nucleotide islocated within the interior of the helix of the duplex RNA. In someembodiments, a size of a bulge of the RNA duplex is reduced. In someembodiments, a bulge of the RNA duplex is removed or maintained.

In some embodiments, splicing at the splice site of the RNA duplex ispromoted. In some embodiments, base stacking of the unpaired bulgednucleotide within an RNA strand of the RNA duplex is increased aftercontacting the SMSM. In some embodiments, the distance of the unpairedbulged nucleotide from a second nucleotide of the duplex RNA isincreased or maintained. In some embodiments, a bulge of the RNA duplexis stabilized after contacting the SMSM. In some embodiments, theunpaired bulged nucleotide is located on an exterior portion of a helixof the duplex RNA. In some embodiments, a size of a bulge of the RNAduplex is increased. In some embodiments, splicing at the splice site ofthe RNA duplex is inhibited. In some embodiments, splicing is inhibitedat the splice site. In some embodiments, base stacking of the unpairedbulged nucleotide within an RNA strand of the RNA duplex is reducedafter contacting the SMSM.

Exemplary sites targeted by the SMSMs described herein include 5′ splicesites, 3′ splice sites, polypyrimidine tracts, branch sites, splicingenhancers and silencer elements. Mutations or aberrant secondary ortertiary RNA structures at hot spots can create mRNA sites or scaffoldsequences that can be targeted. For example, many exons are flanked bythe intronic dinucleotides GT and AG at the 5′ and 3′ splice sites,respectively. For example, mutations or aberrant secondary or tertiaryRNA structures at these sites can cause, e.g., exclusion of an adjacentexon or inclusion of an adjacent intron. Many factors influence thecomplex pre-mRNA splicing process, including several hundred differentproteins, at least five spliceosomal snRNAs, sequences on the mRNA,sequence length, enhancer and silencer elements, and strength ofsplicing signals. Exemplary sites targeted by the SMSMs described hereininclude secondary and sometimes tertiary structures of RNA. For example,exemplary sites targeted by the SMSMs described herein include a stemloop, hairpin, branch point sequence (BPS), polypyrimidine tract (PPT),5′ splice site (5′ss) and 3′ splice site (3′ss), duplex snRNA and splicesites and trans acting protein binding to RNA. The target pre-mRNA cancomprise a defective sequence, such as a sequence that produces adeficient protein, such as a protein with altered function such asenzyme activity, or expression, such as lack of expression. In someembodiments, the defective sequence impacts the structure of the RNA. Insome embodiments, the defect sequence impacts recognition by snRNP.

In addition to consensus splice site sequences, structural constraints,including those resulting from mutations, can affect cis-actingsequences such as exonic/intronic splicing enhancers (ESE/ISE) orsilencer elements (ESS/ISS).

In some embodiments, a mutation in native DNA and/or pre-mRNA, or anaberrant secondary or tertiary structure of RNA, creates a new splicesite sequence. For example, a mutation or aberrant RNA structure maycause native regions of the RNA that are normally dormant, or play norole as splicing elements, to become activated and serve as splice sitesor splice elements. Such splice sites and elements can be referred to as“cryptic”. For example, a native intron may become divided into twoaberrant introns, with a new exon situated there between. For example, amutation may create a new splice site between a native 5′ splice siteand a native branch point. For example, a mutation may activate acryptic branch point sequence between a native splice site and a nativebranch point. For example, a mutation may create a new splice sitebetween a native branch point and a native splice site and may furtheractivate a cryptic splice site and a cryptic branch point sequentiallyupstream from the aberrant mutated splice site.

In some embodiments, a mutation or misexpression of trans-actingproteins that regulate splicing activity may cause native regions of theRNA that are normally dormant, or play no role as splicing elements, tobecome activated and serve as splice sites or splice elements. Forexample, a mutation or misexpression of an SR protein may cause nativeregions of the RNA that are normally dormant, or play no role assplicing elements, to become activated and serve as splice sites orsplice elements.

In some embodiments, a mutation in native DNA and/or pre-mRNA inhibitssplicing at a splice site. For example, a mutation may result in a newsplice site upstream from (i.e., 5′ to) a native splice site sequenceand downstream from (i.e., 3′ to) a native branch point sequence. Thenative splice site sequence and the native branch point sequence mayserve as members of both the native set of splice site sequences and theaberrant set of splice site sequences.

In some embodiments, a native splice element (e.g., a branch point) isalso a member of the set of aberrant splice elements. For example, SMSMsprovided herein can block the native element and activate a crypticelement (e.g., a cryptic 5′ss, a cryptic 3′ ss or a cryptic branchpoint), which may recruit remaining members of the native set of spliceelements to promote correct splicing over incorrect splicing. In someembodiments, an activated cryptic splice element is in an intron. Insome embodiments, an activated cryptic splice element is in an exon. Thecompounds and methods provided herein can be used to block or activate avariety of different splice elements, depending on the type of aberrantsplice element (e.g., mutated splice element or non-mutated spliceelement) and/or depending on regulation of a splice element (e.g.,regulation by upstream signaling pathways). For example, the compoundsand methods provided herein can block a mutated element, a non-mutatedelement, a cryptic element, or a native element; it may block a 5′splice site, a 3′ splice site, or a branch point.

In some embodiments, an alternate splicing event can be modulated byemploying the compounds provided herein. For example, a compoundprovided herein can be introduced into a cell in which a gene is presentthat encodes a pre-mRNA that comprises alternate splice sites. In someembodiments, in the absence of the compound, a first splicing eventoccurs to produce a gene product having a particular function. Forexample, in the presence of the compound provided herein, the firstsplicing event can be inhibited. In some embodiments, in the presence ofthe compound provided herein, the first splicing event can be inhibitedand a second or alternate splicing event occurs, resulting in expressionof the same gene to produce a gene product having a different function.

In some embodiments, a first inhibited splicing event (e.g., a splicingevent inhibited by a mutation, a mutation-induced bulge or anon-mutation induced bulge), is promoted or enhanced in the presence ofa compound provided herein. In some embodiments, the first inhibitedsplicing event (e.g., a splicing event inhibited by a mutation, amutation-induced bulge or a non-mutation induced bulge), is promoted orenhanced in the presence of a compound provided herein. For example, theinhibition of the first splicing event (e.g., a splicing event inhibitedby a mutation, a mutation-induced bulge or a non-mutation induced bulge)can be restored to a corresponding first splicing event that isuninhibited, in the presence of a compound provided herein; or theinhibition of the first splicing event can be decreased, in the presenceof a compound provided herein. In some embodiments, a second oralternate splicing event occurs, resulting in expression of the samegene to produce a gene product having a different function.

Target Polynucleotides

The compounds described herein can modulate splicing of gene products,such as those described herein. In some embodiments, the compoundsdescribed herein are use in the treatment, prevention and/or delay ofprogression of diseases or conditions (e.g., cancer andneurodegenerative diseases). In some embodiments, the compoundsdescribed herein can modulate splicing and induce a transcriptionallyinactive variant or transcript of a gene product, such as thosedescribed herein. In some embodiments, the compounds described hereinmodulate splicing and repress a transcriptionally active variant ortranscript of a gene product, such as those described herein.

Modulation of splicing by the compounds described herein includes, butis not limited to, modulation of naturally occurring splicing, splicingof an RNA expressed in a diseased cell, splicing of cryptic splice sitesequences of an RNA or alternative splicing. Modulation of splicing bythe compounds described herein can restore or promote correct splicingor a desired splicing event. Modulation of splicing by the compoundsdescribed herein includes, but is not limited to, prevention of aberrantsplicing events, e.g., splicing events caused by mutations or aberrantsecondary or tertiary structures of RNA that are associated withconditions and diseases. In some embodiments, the compounds describedherein prevent or inhibit splicing at a splice site sequence. In someembodiments, the compounds described herein promote or increase splicingat a splice site sequence. In some embodiments, the compounds describedherein modulate splicing at a specific splice site sequence.

The compositions and methods described herein can be used to modulatesplicing of a target RNA, e.g., pre-mRNAs, encoded by genes. Examples ofgenes encoding a target RNA, e.g., a pre-mRNA, include, but are notlimited to the genes described herein. Examples of genes encoding atarget RNA of the compositions and methods described herein, e.g., apre-mRNA, include, but are not limited to ABCA4, ABCD1, ACADM, ACADSB,ADA, ADAMTS13, AGL, AGT, ALB, ALDH3A2, ALG6, ANGPTL3, APC, APOA1, APOB,APOC3, AR, ATM, ATP7A, ATP7B, ATR, ATXN2, ATXN3, B2M, BCL2-like 11(BIM), BMP2K, BRCA1, BRCA2, BTK, C3, CACNA1B, CACNA1C, CALCA, CAT, CD33,CD46, CDH1, CDH23, CFB, CFTR, CHM, CLCN1, COL11A1, COL11A2, COL1A1,COL1A2, COL2A1, COL3A1, COL4A5, COL6A1, COL7A1, COL9A2, COLQ, CREBBP,CSTB, CUL4B, CYBB, CYP17, CYP19, CYP27A1, DES, DGAT2, DMD, DUX4, DYSF,EGFR, EMD, ETV4, F11, F13A1, F5, F7, F8, FAH, FANCA, FANCC, FANCG, FBN1,FECH, FGA, FGFR2, FGG, FIX, FLNA, FOXM1, FRAS1, GALC, GBA, GCGR, GH1,GHR, GHV, GLA, HADHA, HBA2, HBB, HEXA, HEXB, HLCS, HMBS, HMGCL, HNF1A,HPRT1, HPRT2, HSF4, HSPG2, HTT, IDH1, IDS, IKBKAP, IL7RA, INSR, ITGB2,ITGB3, ITGB4, JAG1, KLKB1, KRAS, KRT5, L1CAM, LAMA2, LAMA3, LDLR,LGALS3, LMNA, LPA, LPL, LRRK2, MADD, MAPT, MET, MLH1, MSH2, MST1R,MTHFR, MUT, MVK, NF1, NF2, NR1H4, OAT, OPA1, OTC, OXT, PAH, PBGD, PCCA,PDH1, PGK1, PHEX, PKD2, PKLR, PKM1, PKM2, PLEKHM1, PLKR, POMT2, PRDM1,PRKAR1A, PROC, PSEN1, PTCH1, PTEN, PYGM, RP6KA3, RPGR, RSK2, SBCAD,SCN5A, SCNA, SERPINA1, SH2D1A, SLC12A3, SLC6A8, SMN2, SOD1, SPINK5,SPTA1, TMPRSS6, TP53, TRAPPC2, TSC1, TSC2, TSHB, TTN, TTR, UBE3A, UGT1A1and USH2A.

Examples of genes encoding a target RNA, e.g., a pre-mRNA, include, butare not limited to the genes in Table 2B. Examples of genes encoding atarget RNA of the compositions and methods described herein, e.g., apre-mRNA, include, but are not limited to ABCD1, APOB, AR, ATM, BRCA1,C3, CFTR, COL1A1, COL3A1, COL6A1, COL7A1, CYP19, CYP27A1, DMD, F5, F7,FAH, FBN1, FGA, GCK, GHV, HBA2, HBB, HMGCL, HPRT1, HXA, IDS, ITGB2,ITGB3, KRT5, LDLR, LMNA, LPL, MTHFR, NF1, NF2, PBGD, PGK1, PKD1, PTEN,RPGR, TP53, TSC2, UGT1A1 and YGM.

Examples of genes encoding a target RNA, e.g., a pre-mRNA, include, butare not limited to the genes in Table 2C. Examples of genes encoding atarget RNA of the compositions and methods described herein, e.g., apre-mRNA, include, but are not limited to genes encoding a target RNA,e.g., a pre-mRNA, with a splice site comprising a splice site sequenceof AGAguaag. Examples of genes encoding a target RNA of the compositionsand methods described herein, e.g., a pre-mRNA, include, but are notlimited to ABCA9, ABCB1, ABCB5, ACADL, ACSS2, ADAL, ADAM10, ADAM15,ADAMTS20, ADAMTS6, ADAMTS9, ADCY10, ADCY8, AFP, AGL, AHCTF1, AKAP10,AKAP3, ALAS1, ALS2CL, AMBRA1, ANK3, ANTXR2, ANXA10, ANXA11, AP2A2,AP4E1, APOB, ARFGEF1, ARFGEF2, ARHGAP1, ARHGAP18, ARHGEF18, ARHGEF2,ARPC3, ARS2, ASH1L, ASNSD1, ASPM, ATAD5, ATG4A, ATP11C, ATP6V1G3, BBOX1,BCS1L, BMPR2, BRCC3, BRSK2, C10orf137, C11orf70, C12orf51, C13orf1,C13orf15, C14orf118, C15orf29, C15orf42, C16orf33, C16orf38, C16orf48,C18orf8, C19orf42, C1orf107, C1orf114, C1orf130, C1orf149, C1orf27,C1orf71, C1orf94, C1R, C20orf74, C21orf70, C3orf23, C4orf18, C5orf34,C8B, C8orf33, C9orf114, C9orf86, C9orf98, CA11, CAB39, CACNA2D1,CALCOCO2, CAMK1D, CAMKK1, CAPN9, CAPSL, CBX1, CBX3, CCDC102B, CCDC11,CCDC15, CCDC18, CCDC5, CCDC81, CD4, CDC14A, CDC16, CDC2L5, CDC42BPB,CDCA8, CDH10, CDH11, CDH24, CDH8, CDH9, CDK5RAP2, CDK8, CELSR3, CENPI,CENTB2, CENTG2, CEP110, CEP170, CEP192, CETP, CFH, CHAF1A, CHD9, CHIC2,CHN1, CLIC2, CLINT1, CLPB, CMIP, CNOT1, CNOT7, COG3, COL11A1, COL12A1,COL14A1, COL19A1, COL1A1, COL1A2, COL22A1, COL24A1, COL25A1, COL29A1,COL2A1, COL3A1, COL4A1, COL4A2, COL4A5, COL4A6, COL5A2, COL9A1, COMTD1,COPA, COPB2, COPS7B, COPZ2, CPSF2, CPXM2, CR1, CREBBP, CRKRS, CSE1L,CT45-6, CUBN, CUL5, CXorf41, CYP3A4, CYP3A43, CYP3A5, DCC, DCTN3, DDA1,DDX1, DDX24, DDX4, DENND2D, DEPDC2, DHFR, DHRS7, DIP2A, DMD, DNAH3,DNAH8, DNAI1, DNAJA4, DNAJC13, DNAJC7, DNTTIP2, DOCK11, DOCK4, DPP4,DSCC1, DYNC1H1, ECM2, EDEM3, EFCAB3, EFCAB4B, EIF3A, ELA1, ELA2A, EMCN,EML5, ENPP3, EPB41L5, EPHA3, EPHB1, EPHB3, EPS15, ERCC8, ERGIC3, ERMN,ERMP1, ERN1, ERN2, ETS2, EVC2, EX01, EXOC4, F3, FAM13A1, FAM13B1,FAM13C1, FAM184A, FAM19A1, FAM20A, FAM23B, FAM65C, FANCA, FANCM, FANK1,FAR2, FBXO15, FBXO18, FBXO38, FEZ2, FGFR1OP, FGFR1OP2, FGFR2, FGR,FLJ35848, FLJ36070, FLNA, FN1, FNBP1L, FOLH1, FRAS1, FUT9, FZD3, FZD6,GAB1, GALNT3, GART, GAS2L3, GCG, GJA1, GLT8D1, GNAS, GNB5, GOLGB1,GOLT1A, GOLT1B, GPATCH1, GPR160, GRAMD3, GRHPR, GRIA1, GRIA3, GRIA4,GRIN2B, GRM3, GRAM4, GRN, GSDMB, GSTCD, GTPBP4, HDAC3, HDAC5, HDX,HEPACAM2, HERC1, HIPK3, HNRNPH1, HSPA9, HSPG2, HTT, ICA1, IFI44L, IL1R2,IL5RA, IMMT, INPP5D, INTU, IPO4, IPO8, ISL2, IWS1, JAK1, JAK2, KATNAL2,KCNN2, KCNT2, KIAA0256, KIAA0586, KIAA1033, KIAA1219, KIAA1 622, KIF15,KIF16B, KIF5A, KIF5B, KIF9, KIN, KIR2DLSB, KIR3DL2, KIR3DL3, KLF12,KLF3, KPNA5, KREMEN1, KRIT1, KRTCAP2, L1CAM, L3MBTL, L3MBTL2, LACE1,LAMA2, LAMB1, LGMN, LHCGR, LHX6,LIMCH1, LIMK2, LMBRD1, LMBRD2, LMLN,LMO2, LOC390110, LPCAT2, LRP4, LRPPRC, LRRC19, LRRC42, LUM, LVRN, LYST,MADD, MAGI1, MAGT1, MALT1, MAP4K4, MAPK8IP3, MAPK9, MATN2, MCF2L2,MDGA2, MEGF10, MEGF11, MEMO1, MGAM, MGAT4A, MGC34774, MIB1, MIER2, MKL2,MLANA, MLL5, MLX, MME, MPI, MRAP2, MRPL39, MRPS28, MRPS35, MTDH, MTF2,MUC2, MYB, MYCBP2, MYH2, MYO19, MYO3A, MYO9B, MYOM2, MYOM3, NAG, NARG1,NARG2, NCOA1, NDFIP2, NEDD4, NEK1, NEK5, NFIA, NFIX, NFRKB, NKAP, NLRC3,NLRC5, NME7, NOL10, NOS1, NOS2A, NOTCH1, NPM1, NR4A3, NRXN1, NSMAF,NSMCE2, NT5C3, NUBP1, NUBPL, NUMA1, NUP160, NUP98, NUPL1, OBFC2B, OLIG2,OSBPL11, OSBPL8, OSGEPL1, PADI4, PAH, PAN2, PAPOLG, PARVB, PAWR, PCNX,PCOTH, PDCD4, PDE8B, PDIA3, PDK4, PDS5A, PDS5B, PHACTR4, PHKB, PHLDB2,PHTF1, PIAS1, PIGF, PIGN, PIGT, PIK3C2G, PIK3CG, PIK3R1, PIWIL3,PKHD1L1, PLCB1, PLCB4, PLCG1, PLD1, PLEKHA5, PLEKHA7, PLXNC1, POLN,POLR3D, POMT2, POSTN, PPFIA2, PPP1R12A, PPP3CB, PPP4C, PPP4R1L, PPP4R2,PRAME, PRC1, PRIM1, PRIM2, PRKG1, PRMT7, PROCR, PROSC, PROX1, PRPF40B,PRPF4B, PRRG2, PSD3, PSMAL, PTK2, PTK2B, PTPN11, PTPN22, PTPN3, PTPN4,PTPRD, PTPRK, PTPRM, PUS10, PVRL2, QRSL1, RAB11FIP2, RAB23, RB1CC1,RBM39, RBM45, REC8, RFC4, RHPN2, RLN3, RNF32, RNFT1, ROCK1, ROCK2, RP1,RP11-265F1, RP13-36C9, RPAP3, RPN1, RTEL1, RYR3, SAAL1, SAE1, SCN11A,SCN1A, SCN3A, SCO1, SCYL3, SDK2, SEC24A, SEC24D, SEC31A, SEL1L, SENP3,SENP6, SENP7, SETD3, SETD4, SGCE, SGOL2, SGPL1, SH3PXD2A, SH3PXD2B,SH3RF2, SH3TC2, SIPA1L2, SIPA1L3, SKAP1, SKIV2L2, SLC13A1, SLC28A3,SLC38A1, SLC38A4, SLC39A10, SLC4A2, SMARCA1, SMARCA5, SMC5, SNRK,SNRP70, SNX6, SPAG9, SPATA13, SPATA4, SPATS1, SPECC1L, SPP2, SRP72,SSX3, SSX5, SSX9, STAG1, STAMBPL1, STARD6, STK17B, STX3, STXBP1, SUCLG2,SULF2, SUPT16H, SYCP1, SYTL5, TAF2, TBC1D3G, TBC1D8B, TBCEL, TBK1,TCEB3, TCF12, TCP11L2, TDRD3, TEAD1, TET2, TFRC, TG, THOC2, TIAL1,TIAM2, TIMM50, TLK2, TMEM156, TMEM27, TMF1, TNFRSF10A, TNFRSF10B,TNFRSF8, TNK2, TNKS, TNKS2, TOM1L1, TOP2B, TP53INP1, TP63, TRAF3IP3,TRIM44, TRIM65, TRIML1, TRIML2, TRPM7, TTC17, TTLL5, TTN, TTPAL,UHRF1BP1, UNC45B, UNC5C, USP38, USP39, USP6, UTP15, UTP18, UTRN, UTX,UTY, UVRAG, UXT, VAPA, VPS29, VPS35, VTI1A, VTI1B, VWA3B, WDFY2, WDR17,WDR26, WDR44, WDR67, WDTC1, WRNIP1, WWC3,XRN1,XRN2, XX-FW88277, YAKS,ZBTB20, ZC3HAV1, ZC3HC1, ZNF114, ZNF365, ZNF37A, ZNF618 and ZWINT.

Examples of genes encoding a target RNA, e.g., a pre-mRNA, include, butare not limited to the genes in Table 2D. Examples of genes encoding atarget RNA of the compositions and methods described herein, e.g., apre-mRNA, include, but are not limited to genes encoding a target RNA,e.g., a pre-mRNA, with a splice site comprising a splice site sequenceof GGAgtaag. Examples of genes encoding a target RNA of the compositionsand methods described herein, e.g., a pre-mRNA, include, but are notlimited to ABCC9,ACTG2, ADAM22,ADAM32, ADAMTS12, ADCY3,ADRBK2, AFP,AKNA, APOH, ARHGAP26, ARHGAP8, ATG16L2, ATP13A5, B4GALNT3, BBS4, BRSK1,BTAF1, C11orf30, C11orf65, C14orf101, C15orf60, C1orf87, C2orf55,C4orf29, C6orf118, C9orf43, CACHD1, CACNA1G, CACNA1H, CAPN3, CARKD,CCDC131, CCDC146, CD1B, CDK6, CEL, CGN, CGNL1, CHL1, CLEC16A, CLK1,CLPTM1, CMYA5, CNGA3, CNTN6, COL11A1, COL15A1, COL17A1, COL1A1, COL2A1,CRYZ, CSTF3, CYFIP2, CYP24A1, CYP4F2, CYP4F3, DAZ2, DCBLD1, DCUN1D4,DDEF1, DDX1, DHRS9, DMTF1, DOCK10, DPP3, DPY19L2P2, DVL3, EFNA4, EFTUD2,EPHA4, EPHB2, ERBB4, ERCC1, FAM134A, FAM161A, FAM176B, FCGBP, FGD6,FKBP3, GAPDH, GBGT1, GFM1, GPR158, GRIA1, GSTCD, GSTO2, HCK, HLA-DPB1,HLA-G, HLTF, HP1BP3, HPGD, HSF2BP, INTS3, IQGAP2, ITFG1, ITGAL, ITGB1,ITIH1, ITPR2, JMJD1C, KALRN, KCNN2, KIAA0528, KIAA0564, KIAA1166,KIAA1409, KIAA1787, KIF3B, KLHL20, KLK12, LAMA1, LARP7, LENG1,LOC389634, LRWD1, LYN, MAP2K1, MCM6, MEGF10, MGAM, MGAT5, MGC16169,MKKS, MPDZ, MRPL11, MS4A13, MSMB, MTIF2, NDC80, NEB, NEK11, NFE2L2,NFKBIL2, NKAIN2, NLRC3, NLRC5, NLRP13, NLRP7, NLRP8, NT5C, NUDT5, NUP88,OBFC2A, OPN4, OPTN, PARD3, PBRM1, PCBP4, PDE10A, PDLIM5, PDXK, PDZRN3,PELI2, PGM2, PIP5K1A, PITRM1, PKIB, PMFBP1, POMT2, PRKCA, PRODH, PRUNE2,PTPRN2, PTPRT, RALBP1, RALGDS, RBL2, RFT1, RFTN1, RIF1, RMND5B, RNF11,RNGTT, RPS6KA6, RRM1, RRP1B, RTF1, RUFY1, SCN2A, SCN4A, SCN8A, SDK1,SEZ6, SFRS12, SH3BGRL2, SIVA1, SLC22A17, SLC25A14, SLC6A11, SLC6A13,SLC6A6, SMTN, SNCAIP, SNX6, STAT6, SUPT6H, SV2C, SYCP2, SYT6, TAF2,TBC1D26, TBC1D29, TBPL1, TECTB, TEK, TGM7, TGS1, TM4SF20, TM6SF1,TMEM194A, TMEM77, TOM1L2, TP53BP2, TP53I3, TRPM3, TRPM5, TSPAN7, TTLL9,TUSC3, TXNDC10, UCK1, USH2A, USP1, UTP20, VPS39, WDR16, ZC3H7A, ZFYVE1,ZNF169 and ZNF326.

The SMSM compounds and methods of their use described herein canmodulate splicing, such as aberrant splicing of polynucleotide encodedby a gene, e.g., an ABCA4, ABCA9, ABCB1, ABCB5, ABCC9, ABCD1, ACADL,ACADM, ACADSB, ACSS2, ACTG2, ADA, ADAL, ADAM10, ADAM15, ADAM22, ADAM32,ADAMTS12, ADAMTS13, ADAMTS20, ADAMTS6, ADAMTS9, ADCY10, ADCY3, ADCY8,ADRBK2, AFP, AGL, AGT, AHCTF1, AKAP10, AKAP3, AKNA, ALAS1, ALB, ALDH3A2,ALG6, ALS2CL, AMBRA1, ANGPTL3, ANK3, ANTXR2, ANXA10, ANXA11, AP2A2,AP4E1, APC, APOA1, APOB, APOC3, APOH, AR, ARFGEF1, ARFGEF2, ARHGAP1,ARHGAP18, ARHGAP26, ARHGAP8, ARHGEF18, ARHGEF2, ARPC3, ARS2, ASH1L,ASNSD1, ASPM, ATAD5, ATG16L2, ATG4A, ATM, ATP11C, ATP13A5, ATP6V1G3,ATP7A, ATP7B, ATR, ATXN2, ATXN3, B2M, B4GALNT3, BBOX1, BBS4, BCL2-like11 (BIM), BCS1L, BMP2K, BMPR2, BRCA1, BRCA2, BRCC3, BRSK1, BRSK2, BTAF1,BTK, C10orf137, C11orf30, C11orf65, C11orf70, C12orf51, C13orf1,C13orf15, C14orf101, C14orf118, C15orf29, C15orf42, C15orf60, C16orf33,C16orf38, C16orf48, C18orf8, C19orf42, C1orf107, C1orf114,C1orf130,C1orf149, C1orf27, C1orf71, C1orf87, C1or194, C1R, C20orf74, C21orf70,C2orf55, C3, C3orf23, C4orf18, C4orf29, C5orf34, C6orf118, C8B, C8orf33,C9orf114, C9orf43, C9orf86, C9orf98, CA11, CAB39, CACHD1, CACNA1B,CACNA1C, CACNA1G, CACNA1H, CACNA2D1, CALCA, CALCOCO2, CAMK1D, CAMKK1,CAPN3, CAPN9, CAPSL, CARKD, CAT, CBX1, CBX3, CCDC102B, CCDC11, CCDC131,CCDC146, CCDC15, CCDC18, CCDC5, CCDC81, CD1B, CD33, CD4, CD46, CDC14A,CDC16, CDC2L5, CDC42BPB, CDCA8, CDH1, CDH10, CDH11, CDH23, CDH24, CDH8,CDH9, CDK5RAP2, CDK6, CDK8, CEL, CELSR3, CENPI, CENTB2, CENTG2, CEP110,CEP170, CEP192, CETP, CFB, CFH, CFTR, CGN, CGNL1, CHAF1A, CHD9, CHIC2,CHL1, CHM, CHN1, CLCN1, CLEC16A, CLIC2, CLINT1, CLK1, CLPB, CLPTM1,CMIP, CMYA5, CNGA3, CNOT1, CNOT7, CNTN6, COG3, COL11A1, COL11A2,COL12A1, COL14A1, COL15A1, COL17A1, COL19A1, COL1A1, COL1A2, COL22A1,COL24A1, COL25A1, COL29A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A5,COL4A6, COL5A2, COL6A1, COL7A1, COL9A1, COL9A2, COLQ, COMTD1, COPA,COPB2, COPS7B, COPZ2, CPSF2, CPXM2, CR1, CREBBP, CRKRS, CRYZ, CSE1L,CSTB, CSTF3, CT45-6, CUBN, CUL4B, CUL5, CXorf41, CYBB, CYFIP2, CYP17,CYP19, CYP24A1, CYP27A1, CYP3A4, CYP3A43, CYP3A5, CYP4F2, CYP4F3, DAZ2,DCBLD1, DCC, DCTN3, DCUN1D4, DDA1, DDEF1, DDX1, DDX24, DDX4, DENND2D,DEPDC2, DES, DGAT2, DHFR, DHRS7, DHRS9, DIP2A, DMD, DMTF1, DNAH3, DNAH8,DNAI1, DNAJA4, DNAJC13, DNAJC7, DNTTIP2, DOCK10, DOCK11, DOCK4, DPP3,DPP4, DPY19L2P2, DSCC1, DDX4, DVL3, DYNC1H1, DYSF, ECM2, EDEM3, EFCAB3,EFCAB4B, EFNA4, EFTUD2, EGFR, EIF3A, ELA1, ELA2A, EMCN, EMD, EML5,ENPP3, EPB41L5, EPHA3, EPHA4, EPHB1, EPHB2, EPHB3, EPS1 5, ERBB4, ERCC1,ERCC8, ERGIC3, ERMN, ERMP1, ERN1, ERN2, ETS2, ETV4, EVC2, EXO1, EXOC4,F11, F13A1, F3, F5, F7, F8, FAH, FAM134A, FAM13A1, FAM13B1, FAM13C1,FAM161A, FAM176B, FAM184A, FAM19A1, FAM20A, FAM23B, FAM65C, FANCA,FANCC, FANCG, FANCM, FANK1, FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGBP,FECH, FEZ2, FGA, FGD6, FGFR1OP, FGFR1OP2, FGFR2, FGG, FGR, FIX, FKBP3,FLJ35848, FLJ36070, FLNA, FN1, FNBP1L, FOLH1, Foxy1, FRAS1, FUT9, FZD3,FZD6, GAB1, GALC, GALNT3, GAPDH, GART, GAS2L3, GBA, GBGT1, GCG, GCGR,GCK, GFM1, GH1, GHR, GHV, GJA1, GLA, GLT8D1, GNAS, GNB5, GOLGB1, GOLT1A,GOLT1B, GPATCH1, GPR158, GPR160, GRAMD3, GRHPR, GRIA1, GRIA3, GRIA4,GRIN2B, GRM3, GRM4, GRN, GSDMB, GSTCD, GSTO2, GTPBP4, HADHA, HBA2, HBB,HCK, HDAC3, HDAC5, HDX, HEPACAM2, HERC1, HEXA, HEXB, HIPK3, HLA-DPB1,HLA-G, HLCS, HLTF, HMBS, HMGCL, HNF1A, HNRNPH1, HP1BP3, HPGD, HPRT1,HPRT2, HSF2BP, HSF4, HSPA9, HSPG2, HTT, HXA, ICA1, IDH1, IDS, IFI44L,IKBKAP, IL1R2, IL5RA, IL7RA, IMMT, INPP5D, INSR, INTS3, INTU, IPO4,IPO8, IQGAP2, ISL2, ITFG1, ITGAL, ITGB1, ITGB2, ITGB3, ITGB4, ITIH1,ITPR2, IWS1, JAG1, JAK1, JAK2, JMID1C, KALRN, KATNAL2, KCNN2, KCNT2,KIAA0256, KIAA0528, KIAA0564, KIAA0586, KIAA1033, KIAA1166, KIAA1219,KIAA1409, KIAA1622, KIAA1787, KIF15, KIF16B, KIF3B, KIF5A, KIF5B, KIF9,KIN, KIR2DL5B, KIR3DL2, KIR3DL3, KLF12, KLF3, KLHL20, KLK12, KLKB1,KPNA5, KRAS, KREMEN1, KRIT1, KRT5, KRTCAP2, L1CAM, L3MBTL, L3MBTL2,LACE1, LAMA1, LAMA2, LAMA3, LAMB1, LARP7, LDLR, LENG1, LGALS3, LGMN,LHCGR, LHX6, LIMCH1, LIMK2, LMBRD1, LMBRD2, LMLN, LMNA, LMO2, LOC389634,LOC390110, LPA, LPCAT2, LPL, LRP4, LRPPRC, LRRC19, LRRC42, LRRK2, LRWD1,LUM, LVRN, LYN, LYST, MADD, MAGI1, MAGT1, MALT1, MAP2K1, MAP4K4,MAPK8IP3, MAPK9, MAPT, MATN2, MCF2L2, MCM6, MDGA2, MEGF10, MEGF11,MEMO1, MET, MGAM, MGAT4A, MGAT5, MGC16169, MGC34774, MIB1, MIER2, MKKS,MKL2, MLANA, MLH1, MLL5, MLX, MME, MPDZ, MPI, MRAP2, MRPL11, MRPL39,MRPS28, MRPS35, MS4A13, MSH2, MSMB, MST1R, MTDH, MTF2, MTHFR, MTIF2,MUC2, MUT, MVK, MYB, MYCBP2, MYH2, MYO19, MYO3A, MYO9B, MYOM2, MYOM3,NAG, NARG1, NARG2, NCOA1, NDC80, NDFIP2, NEB, NEDD4, NEK1, NEK11, NEK5,NF1, NF2, NFE2L2, NFIA, NFIX, NFKBIL2, NFRKB, NKAIN2, NKAP, NLRC3,NLRC5, NLRP13, NLRP7, NLRP8, NME7, NOL10, NOS1, NOS2A, NOTCH1,NPM1,NR1H4, NR4A3, NRXN1, NSMAF, NSMCE2, NT5C, NT5C3, NUBP1, NUBPL, NUDT5,NUMA1, NUP160, NUP88, NUP98, NUPL1, OAT, OBFC2A, OBFC2B, OLIG2, OPA1,OPN4, OPTN, OSBPL11, OSBPL8, OSGEPL1, OTC, OXT, PADI4, PAH, PAN2,PAPOLG, PARD3, PARVB, PAWR, PBGD, PBRM1, PCBP4, PCCA, PCNX, PCOTH,PDCD4, PDE10A, PDE8B, PDH1, PDIA3, PDK4, PDLIM5, PDS5A, PDS5B, PDXK,PDZRN3, PELI2, PGK1, PGM2, PHACTR4, PHEX, PHKB, PHLDB2, PHTF1, PIAS1,PIGF, PIGN, PIGT, PIK3C2G, PIK3CG, PIK3R1, PIP5K1A, PITRM1, PIWIL3,PKD1, PKD2, PKHD1L1, PKIB, PKLR, PKM1, PKM2, PLCB1, PLCB4, PLCG1, PLD1,PLEKHA5, PLEKHA7, PLEKHM1, PLKR, PLXNC1, PMFBP1, POLN, POLR3D, POMT2,POSTN, PPFIA2, PPP1R12A, PPP3CB, PPP4C, PPP4R1L, PPP4R2, PRAME, PRC1,PRDM1, PRIM1, PRIM2, PRKAR1A, PRKCA, PRKG1, PRMT7, PROC, PROCR, PRODH,PROSC, PROX1, PRPF40B, PRPF4B, PRRG2, PRUNE2, PSD3, PSEN1, PSMAL, PTCH1,PTEN, PTK2, PTK2B, PTPN11, PTPN22, PTPN3, PTPN4, PTPRD, PTPRK, PTPRM,PTPRN2, PTPRT, PUS10, PVRL2, PYGM, QRSL1, RAB11FIP2, RAB23, RALBP1,RALGDS, RB1CC1, RBL2, RBM39, RBM45, REC8, RFC4, RFT1, RFTN1, RHPN2,RIF1, RLN3, RMND5B, RNF11, RNF32, RNFT1, RNGTT, ROCK1, ROCK2, RP1,RP11-265F1, RP13-36C9, RP6KA3, RPAP3, RPGR, RPN1, RPS6KA6, RRM1, RRP1B,RSK2, RTEL1, RTF1, RUFY1, RYR3, SAAL1, SAE1, SBCAD, SCN11A, SCN1A,SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCNA, SCO1, SCYL3, SDK1, SDK2,SEC24A, SEC24D, SEC31A, SEL1L, SENP3, SENP6, SENP7, SERPINA1, SETD3,SETD4, SEZ6, SFRS12, SGCE, SGOL2, SGPL1, SH2D1A, SH3BGRL2, SH3PXD2A,SH3PXD2B, SH3RF2, SH3TC2, SIPA1L2, SIPA1L3, SIVA1, SKAP1, SKIV2L2,SLC12A3, SLC13A1, SLC22A17, SLC25A14, SLC28A3, SLC38A1, SLC38A4,SLC39A10, SLC4A2, SLC6A11, SLC6A13, SLC6A6, SLC6A8, SMARCA1, SMARCA5,SMC5, SMN2, SMTN, SNCAIP, SNRK, SNRP70, SNX6, SOD1, SPAG9, SPATA13,SPATA4, SPATS1, SPECC1L, SPINK5, SPP2, SPTA1, SRP72, SSX3, SSX5, SSX9,STAG1, STAMBPL1, STARD6, STAT6, STK17B, STX3, STXBP1, SUCLG2, SULF2,SUPT16H, SUPT6H, SV2C, SYCP1, SYCP2, SYT6, SYTL5, TAF2, TBC1D26,TBC1D29, TBC1D3G, TBC1D8B, TBCEL, TBK1, TBPL1, TCEB3, TCF12, TCP11L2,TDRD3, TEAD1, TECTB, TEK, TET2, TFRC, TG, TGM7, TGS1, THOC2, TIAL1,TIAM2, TIMM50, TLK2, TM4SF20, TM6SF1, TMEM156, TMEM194A, TMEM27, TMEM77,TMF1, TMPRSS6, TNFRSF10A, TNFRSF10B, TNFRSF8, TNK2, TNKS, TNKS2, TOM1L1,TOM1L2, TOP2B, TP53, TP53BP2, TP53I3, TP53INP1, TP63, TRAF3IP3, TRAPPC2,TRIM44, TRIM65, TRIML1, TRIML2, TRPM3, TRPM5, TRPM7, TSC1, TSC2, TSHB,TSPAN7, TTC17, TTLL5, TTLL9, TTN, TTPAL, TTR, TUSC3, TXNDC10, UBE3A,UCK1, UGT1A1, UHRF1BP1, UNC45B, UNC5C, USH2A, USP1, USP38, USP39, USP6,UTP15, UTP18, UTP20, UTRN, UTX, UTY, UVRAG, UXT, VAPA, VPS29, VPS35,VPS39, VTI1A, VTI1B, VWA3B, WDFY2, WDR16, WDR17, WDR26, WDR44, WDR67,WDTC1, WRNIP1, WWC3, XRN1, XRN2, XX-FW88277, YARS, YGM, ZBTB20, ZC3H7A,ZC3HAV1, ZC3HC1, ZFYVE1, ZNF114, ZNF169, ZNF326, ZNF365, ZNF37A, ZNF618or ZWINT gene.

For example, provided herein are splice modulating compounds thatmodulate splicing, such as aberrant splicing of ABCA4, ABCA9, ABCB1,ABCB5, ABCC9, ABCD1, ACADL, ACADM, ACADSB, ACSS2, ACTG2, ADA, ADAL,ADAM10, ADAM15, ADAM22, ADAM32, ADAMTS12, ADAMTS13, ADAMTS20, ADAMTS6,ADAMTS9, ADCY10, ADCY3, ADCY8, ADRBK2, AFP, AGL, AGT, AHCTF1, AKAP10,AKAP3, AKNA, ALAS1, ALB, ALDH3A2, ALG6, ALS2CL, AMBRA1, ANGPTL3, ANK3,ANTXR2, ANXA10, ANXA11, AP2A2, AP4E1, APC, APOA1, APOB, APOC3, APOH, AR,ARFGEF1, ARFGEF2, ARHGAP1, ARHGAP18, ARHGAP26, ARHGAP8, ARHGEF18,ARHGEF2, ARPC3, ARS2, ASH1L, ASNSD1, ASPM, ATAD5, ATG16L2, ATG4A, ATM,ATP11C, ATP13A5, ATP6V1G3, ATP7A, ATP7B, ATR, ATXN2, ATXN3, B2M,B4GALNT3, BBOX1, BBS4, BCL2-like 11 (BIM), BCS1L, BMP2K, BMPR2, BRCA1,BRCA2, BRCC3, BRSK1, BRSK2, BTAF1, BTK, C10orf137, C11orf30, C11orf65,C11orf70, C12orf51, C13orf1, C13orf15, C14orf101, C14orf118, C15orf29,C15orf42, C15orf60, C16orf33, C16orf38, C16orf48, C18orf8, C19orf42,C1orf107, C1orf114, C1orf130, C1orf149, C1orf27, C1orf71, C1orf87,C1orf94, C1R, C20orf74, C21orf70, C2orf55, C3, C3orf23, C4orf18,C4orf29, C5orf34, C6orf118, C8B, C8orf33, C9orf114, C9orf43, C9orf86,C9orf98, CA11, CAB39, CACHD1, CACNA1B, CACNA1C, CACNA1G, CACNA1H,CACNA2D1, CALCA, CALCOCO2, CAMK1D, CAMKK1, CAPN3, CAPN9, CAPSL, CARKD,CAT, CBX1, CBX3, CCDC102B, CCDC11, CCDC131, CCDC146, CCDC15, CCDC18,CCDC5, CCDC81, CD1B, CD33, CD4, CD46, CDC14A, CDC16, CDC2L5, CDC42BPB,CDCA8, CDH1, CDH10, CDH11, CDH23, CDH24, CDH8, CDH9, CDK5RAP2, CDK6,CDK8, CEL, CELSR3, CENPI, CENTB2, CENTG2, CEP110, CEP170, CEP192, CETP,CFB, CFH, CFTR, CGN, CGNL1, CHAF1A, CHD9, CHIC2, CHL1, CHM, CHN1, CLCN1,CLEC16A, CLIC2, CLINT1, CLK1, CLPB, CLPTM1, CMIP, CMYA5, CNGA3, CNOT1,CNOT7, CNTN6, COG3, COL11A1, COL11A2, COL12A1, COL14A1, COL15A1,COL17A1, COL19A1, COL1A1, COL1A2, COL22A1, COL24A1, COL25A1, COL29A1,COL2A1, COL3A1, COL4A1, COL4A2, COL4A5, COL4A6, COL5A2, COL6A1, COL7A1,COL9A1, COL9A2, COLQ, COMTD1, COPA, COPB2, COPS7B, COPZ2, CPSF2, CPXM2,CR1, CREBBP, CRKRS, CRYZ, CSE1L, CSTB, CSTF3, CT45-6, CUBN, CUL4B, CUL5,CXorf41, CYBB, CYFIP2, CYP17, CYP19, CYP24A1, CYP27A1, CYP3A4, CYP3A43,CYP3A5, CYP4F2, CYP4F3, DAZ2, DCBLD1, DCC, DCTN3, DCUN1D4, DDA1, DDEF1,DDX1, DDX24, DDX4, DENND2D, DEPDC2, DES, DGAT2, DHFR, DHRS7, DHRS9,DIP2A, DMD, DMTF1, DNAH3, DNAH8, DNAI1, DNAJA4, DNAJC13, DNAJC7,DNTTIP2, DOCK10, DOCK11, DOCK4, DPP3, DPP4, DPY19L2P2, DSCC1, DUX4,DVL3, DYNC1H1, DYSF, ECM2, EDEM3, EFCAB3, EFCAB4B, EFNA4, EFTUD2, EGFR,EIF3A, ELA1, ELA2A, EMCN, EMD, EML5, ENPP3, EPB41L5, EPHA3, EPHA4,EPHB1, EPHB2, EPHB3, EPS15, ERBB4, ERCC1, ERCC8, ERGIC3, ERMN, ERMP1,ERN1, ERN2, ETS2, ETV4, EVC2, EXO1, EXOC4, F11, F13A1, F3, F5, F7, F8,FAH, FAM134A, FAM13A1, FAM13B1, FAM13C1, FAM161A, FAM176B, FAM184A,FAM19A1, FAM20A, FAM23B, FAM65C, FANCA, FANCC, FANCG, FANCM, FANK1,FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGBP, FECH, FEZ2, FGA, FGD6,FGFR1OP, FGFR1OP2, FGFR2, FGG, FGR, FIX, FKBP3, FLJ35848, FLJ36070,FLNA, FN1, FNBP1L, FOLH1, FOXM1, FRAS1, FUT9, FZD3, FZD6, GAB1, GALC,GALNT3, GAPDH, GART, GAS2L3, GBA, GBGT1, GCG, GCGR, GCK, GFM1, GH1, GHR,GHV, GJA1, GLA, GLT8D1, GNAS, GNB5, GOLGB1, GOLT1A, GOLT1B, GPATCH1,GPR158, GPR160, GRAMD3, GRHPR, GRIA1, GRIA3, GRIA4, GRIN2B, GRM3, GRM4,GRN, GSDMB, GSTCD, GSTO2, GTPBP4, HADHA, HBA2, HBB, HCK, HDAC3, HDAC5,HDX, HEPACAM2, HERC1, HEXA, HEXB, HIPK3, HLA-DPB1, HLA-G, HLCS, HLTF,HMBS, HMGCL, HNF1A, HNRNPH1, HP1BP3, HPGD, HPRT1, HPRT2, HSF2BP, HSF4,HSPA9, HSPG2, HTT, HXA, ICA1, IDH1, IDS, IFI44L, IKBKAP, IL1R2, IL5RA,IL7RA, IMMT, INPP5D, INSR, INTS3, INTU, IPO4, IPO8, IQGAP2, ISL2, ITFG1,ITGAL, ITGB1, ITGB2, ITGB3, ITGB4, ITIH1, ITPR2, IWS1, JAG1, JAK1, JAK2,JMJD1C, KALRN, KATNAL2, KCNN2, KCNT2, KIAA0256, KIAA0528, KIAA0564,KIAA0586, KIAA1033, KIAA1166, KIAA1219, KIAA1409, KIAA1622, KIAA1787,KIF15, KIF16B, KIF3B, KIF5A, KIF5B, KIF9, KIN, KIR2DL5B, KIR3DL2,KIR3DL3, KLF12, KLF3, KLHL20, KLK12, KLKB1, KPNA5, KRAS, KREMEN1, KRIT1,KRT5, KRTCAP2, L1CAM, L3MBTL, L3MBTL2, LACE1, LAMA1, LAMA2, LAMA3,LAMB1, LARP7, LDLR, LENG1, LGALS3, LGMN, LHCGR, LHX6, LIMCH1, LIMK2,LMBRD1, LMBRD2, LMLN, LMNA, LMO2, LOC389634, LOC390110, LPA, LPCAT2,LPL, LRP4, LRPPRC, LRRC19, LRRC42, LRRK2, LRWD1, LUM, LVRN, LYN, LYST,MADD, MAGI1, MAGT1, MALT1, MAP2K1, MAP4K4, MAPK8IP3, MAPK9, MAPT, MATN2,MCF2L2, MCM6, MDGA2, MEGF10, MEGF11, MEMO1, MET, MGAM, MGAT4A, MGAT5,MGC16169, MGC34774, MIB1, MIER2, MKKS, MKL2, MLANA, MLH1, MLL5, MLX,MME, MPDZ, MPI, MRAP2, MRPL11, MRPL39, MRPS28, MRPS35, MS4A13, MSH2,MSMB, MST1R, MTDH, MTF2, MTHFR, MTIF2, MUC2, MUT, MVK, MYB, MYCBP2,MYH2, MYO19, MYO3A, MYO9B, MYOM2, MYOM3, NAG, NARG1, NARG2, NCOA1,NDC80, NDFIP2, NEB, NEDD4, NEK1, NEK11, NEK5, NF1, NF2, NFE2L2, NFIA,NFIX, NFKBIL2, NFRKB, NKAIN2, NKAP, NLRC3, NLRC5, NLRP13, NLRP7, NLRP8,NME7, NOL10, NOS1, NOS2A, NOTCH1, NPM1, NR1H4, NR4A3, NRXN1, NSMAF,NSMCE2, NT5C, NT5C3, NUBP1, NUBPL, NUDT5, NUMA1, NUP160, NUP88, NUP98,NUPL1, OAT, OBFC2A, OBFC2B, OLIG2, OPA1, OPN4, OPTN, OSBPL11, OSBPL8,OSGEPL1, OTC, OXT, PADI4, PAH, PAN2, PAPOLG, PARD3, PARVB, PAWR, PBGD,PBRM1, PCBP4, PCCA, PCNX, PCOTH, PDCD4, PDE10A, PDE8B, PDH1, PDIA3,PDK4, PDLIM5, PDS5A, PDS5B, PDXK, PDZRN3, PELI2, PGK1, PGM2, PHACTR4,PHEX, PHKB, PHLDB2, PHTF1, PIAS1, PIGF, PIGN, PIGT, PIK3C2G, PIK3CG,PIK3R1, PIP5K1A, PITRM1, PIWIL3, PKD1, PKD2, PKHD1L1, PKIB, PKLR, PKM1,PKM2, PLCB1, PLCB4, PLCG1, PLD1, PLEKHA5, PLEKHA7, PLEKHM1, PLKR,PLXNC1, PMFBP1, POLN, POLR3D, POMT2, POSTN, PPFIA2, PPP1R12A, PPP3CB,PPP4C, PPP4R1L, PPP4R2, PRAME, PRC1, PRDM1, PRIM1, PRIM2, PRKAR1A,PRKCA, PRKG1, PRMT7, PROC, PROCR, PRODH, PROSC, PROX1, PRPF40B, PRPF4B,PRRG2, PRUNE2, PSD3, PSEN1, PSMAL, PTCH1, PTEN, PTK2, PTK2B, PTPN11,PTPN22, PTPN3, PTPN4, PTPRD, PTPRK, PTPRM, PTPRN2, PTPRT, PUS10, PVRL2,PYGM, QRSL1, RAB11FIP2, RAB23, RALBP1, RALGDS, RB1CC1, RBL2, RBM39,RBM45, REC8, RFC4, RFT1, RFTN1, RHPN2, RIF1, RLN3, RMND5B, RNF11, RNF32,RNFT1, RNGTT, ROCK1, ROCK2, RP1, RP11-265F1, RP13-36C9, RP6KA3, RPAP3,RPGR, RPN1, RPS6KA6, RRM1, RRP1B, RSK2, RTEL1, RTF1, RUFY1, RYR3, SAAL1,SAE1, SBCAD, SCN11A, SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCNA,SCO1, SCYL3, SDK1, SDK2, SEC24A, SEC24D, SEC31A, SEL1L, SENP3, SENP6,SENP7, SERPINA1, SETD3, SETD4, SEZ6, SFRS12, SGCE, SGOL2, SGPL1, SH2D1A,SH3BGRL2, SH3PXD2A, SH3PXD2B, SH3RF2, SH3TC2, SIPA1L2, SIPA1L3, SIVA1,SKAP1, SKIV2L2, SLC12A3, SLC13A1, SLC22A17, SLC25A14, SLC28A3, SLC38A1,SLC38A4, SLC39A10, SLC4A2, SLC6A11, SLC6A13, SLC6A6, SLC6A8, SMARCA1,SMARCA5, SMC5, SMN2, SMTN, SNCAIP, SNRK, SNRP70, SNX6, SOD1, SPAG9,SPATA13, SPATA4, SPATS1, SPECC1L, SPINK5, SPP2, SPTA1, SRP72, SSX3,SSX5, SSX9, STAG1, STAMBPL1, STARD6, STAT6, STK17B, STX3, STXBP1,SUCLG2, SULF2, SUPT16H, SUPT6H, SV2C, SYCP1, SYCP2, SYT6, SYTL5, TAF2,TBC1D26, TBC1D29, TBC1D3G, TBC1D8B, TBCEL, TBK1, TBPL1, TCEB3, TCF12,TCP11L2, TDRD3, TEAD1, TECTB, TEK, TET2, TFRC, TG, TGM7, TGS1, THOC2,TIAL1, TIAM2, TIMM50, TLK2, TM4SF20, TM6SF1, TMEM156, TMEM194A, TMEM27,TMEM77, TMF1, TMPRSS6, TNFRSF10A, TNFRSF10B, TNFRSF8, TNK2, TNKS, TNKS2,TOM1L1, TOM1L2, TOP2B, TP53, TP53BP2, TP53I3, TP53INP1, TP63, IRAF3IP3,TRAPPC2, TRIM44, TRIM65, TRIML1, TRIML2, TRPM3, TRPM5, TRPM7, TSC1,TSC2, TSHB, TSPAN7, TTC17, TTLL5, TTLL9, TTN, TTPAL, TTR, TUSC3,TXNDC10, UBE3A, UCK1, UGT1A1, UHRF1BP1, UNC45B, UNC5C, USH2A, USP1,USP38, USP39, USP6, UTP15, UTP18, UTP20, UTRN, UTX, UTY, UVRAG, UXT,VAPA, VPS29, VPS35, VPS39, VTI1A, VTI1B, VWA3B, WDFY2, WDR16, WDR17,WDR26, WDR44, WDR67, WDTC1, WRNIP1, WWC3, XRN1, XRN2, XX-FW88277, YARS,YGM, ZBTB20, ZC3H7A, ZC3HAV1, ZC3HC1, ZFYVE1, ZNF114, ZNF169, ZNF326,ZNF365, ZNF37A, ZNF618 or a ZWINT mRNA, such as pre-mRNA.

In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ABCA4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ABCA9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ABCB1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ABCB5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ABCC9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ABCD1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ACADL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ACADM. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ACADSB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ACSS2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ACTG2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ADA. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ADAL. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAM10. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAM15. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAM22. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAM32. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAMTS12. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAMTS13. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAMTS20. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAMTS6. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAMTS9. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADCY10. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADCY3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ADCY8. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofADRBK2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of AFP. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of AGL. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of AGT. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of AHCTF1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of AKAP10. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of AKAP3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of AKNA. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of ALAS1.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ALB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ALDH3A2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ALG6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ALS2CL. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of AMBRA1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ANGPTL3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ANK3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ANTXR2. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofANXA10. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ANXA11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of AP2A2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of AP4E1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of APC. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of APOA1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of APOB. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of APOC3. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofAPOH. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of AR. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARFGEF1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARFGEF2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGAP1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGAP18. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGAP26. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGAP8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGEF18. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGEF2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARPC3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARS2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ASH1L. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ASNSD1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ASPM. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ATAD5. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofATG16L2. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of ATG4A. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ATM. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ATP11C. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ATP13A5. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ATP6V1G3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ATP7A. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ATP7B. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofATR. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ATXN2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ATXN3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of B2M. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of B4GALNT3. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of BBOX1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of BBS4. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofBCL2like 11 (BIM). In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofBCS1L. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of BMP2K. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BMPR2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BRCA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BRCA2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BRCC3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BRSK1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BRSK2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BTAF1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BTK. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of C10orf137. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf30. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf65. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf70. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C12orf51. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C13orf1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C13orf15. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C14orf101. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C14orf118. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C15orf29. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C15orf42. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C15orf60. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C16orf33. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C16orf38. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C 16orf48. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C18orf8. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C19orf42. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C1orf107. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C1orf114. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C1orf130. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C1orf149. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C1orf27. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C1orf71. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C1orf87. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C1orf94. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C1R. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of C20orf74. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of C21orf70. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of C2orf55. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA of C3.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of C3orf23. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of C4orf18. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of C4orf29. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of C5orf34. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of C6orf118. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of C8B. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of C8orf33. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C9orf114. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C9orf43. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C9orf86. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C9orf98. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CA11. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CAB39. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCACHD1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CACNA1B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CACNA1C. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CACNA1G. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CACNA1H. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CACNA2D1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CALCA. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CALCOCO2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAMK1D. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAMKK1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAPN3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAPN9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAPSL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CARKD. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAT. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CBX1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CBX3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CCDC102B. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of CCDC11. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCCDC131. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of CCDC146. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CCDC15. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CCDC18. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CCDC5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CCDC81. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CD1B. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CD33. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CD4. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CD46. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofCDC14A. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CDC16. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CDC2L5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CDC42BPB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CDCA8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CDH1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CDH10. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CDH11. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CDH23. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCDH24. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CDH8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CDH9. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CDK5RAP2. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CDK6. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CDK8. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of CEL.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CELSR3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CENPI. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CENTB2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CENTG2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CEP110. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CEP170. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CEP192. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CETP. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CFB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CFH. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CFTR. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of CGN.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CGNL1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CHAF1A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CHD9. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CHIC2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CHL1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CHM. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of CHN1.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CLCN1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CLEC16A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CLIC2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CLINT1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CLK1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CLPB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CLPTM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CMIP. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CMYA5. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCNGA3. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CNOT1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CNOT7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CNTN6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of COG3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of COL11A1. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL11A2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL12A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL14A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL15A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL17A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL19A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL1A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL1A2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL22A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL24A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL25A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL29A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL2A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL3A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL4A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL4A2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL4A5. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL4A6. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL5A2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL6A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL7A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL9A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL9A2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COLQ. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of COMTD1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCOPA. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of COPB2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of COPS7B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of COPZ2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CPSF2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CPXM2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CR1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CREBBP. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CRKRS. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CRYZ. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of CSE1L.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CSTB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CSTF3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CT45-6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CUBN. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CUL4B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CUL5. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CXorf41. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCYBB. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CYFIP2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP17. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP19. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP24A1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP27A1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP3A4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP3A43. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP3A5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP4F2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP4F3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DAZ2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of DCBLD1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of DCC. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of DCTN3. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofDCUN1D4. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of DDA 1. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DDEF1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DDX1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of DDX24. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of DDX4. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of DENND2D. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofDEPDC2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of DES. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DGAT2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DHFR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of DHRS7. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of DHRS9. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of DIP2A. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofDMD. For example, the SMSM compounds and methods of their use describedherein can modulate splicing of exon 51a pre-mRNA of DMD. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DMTF1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAH3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAH8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAI1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAJA4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAJC13. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAJC7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNTTIP2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DOCK10. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DOCK11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DOCK4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DPP3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of DPP4. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of DPY19L2P2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of DSCC1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of DUX4. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of DVL3.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of DYNC1H1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DYSF. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ECM2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of EDEM3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of EFCAB3. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofEFCAB4B. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of EFNA4. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EFTUD2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EGFR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of EIF3A. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ELA1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ELA2A. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofEMCN. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of EMD. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EML5. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ENPP3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of EPB41L5. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of EPHA3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of EPHA4. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofEPHB1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of EPHB2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EPHB3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EPS15. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ERBB4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ERCC1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ERCC8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ERGIC3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ERMN. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ERMP1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ERN1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ERN2. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of ETS2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ETV4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EVC2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of EXO1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of EXOC4. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of F11. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of F13A1.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of F3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of F5. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of F7. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of F8. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of FAH. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofFAM134A. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of FAM13A1. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM13B1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM13C1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM161A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM176B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM184A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM19A1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM20A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM23B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM65C. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FANCA. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FANCC. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FANCG. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FANCM. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FANK1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAR2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of FBN1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FBXO15. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FBXO18. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FBXO38. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FCGBP. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of FECH. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of FEZ2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of FGA. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FGD6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of FGFR1OP. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FGFR1OP2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FGFR2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of FGG. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of FGR.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of FIX. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FKBP3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FLJ35848. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FLJ36070. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FLNA. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of FN1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FNBP1L. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FOLH1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of FOXM1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofFRAS1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of FUT9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FZD3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of FZD6. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of GAB1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of GALC. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofGALNT3. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of GAPDH. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GART. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of GAS2L3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of GBA. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of GBGT1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofGCG. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of GCGR. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GCK. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of GFM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of GH1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of GHR. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of GHV.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of GJA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GLA. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of GLT8D1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of GNAS. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of GNB5. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofGOLGB1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of GOLT1A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GOLT1B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GPATCH1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GPR158. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GPR160. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRAMD3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRHPR. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRIA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRIA3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRIA4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRIN2B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRM3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of GRM4. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of GRN. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of GSDMB. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofGSTCD. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of GSTO2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GTPBP4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HADHA. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HBA2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of HBB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of HCK. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of HDAC3. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofHDAC5. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of HDX. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HEPACAM2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HERC1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HEXA. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of HEXB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of HIPK3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of HLA-DPB1. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of HLA-G. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofHLCS. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of HLTF. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HMBS. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of HMGCL. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of HNF1A. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of HNRNPH1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofHP1BP3. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of HPGD. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HPRT1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HPRT2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HSF2BP. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HSF4. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of HSPA9. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of HSPG2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of HTT. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of HXA.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ICA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of IDH1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of IDS. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of IFI44L. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of IKBKAP. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of IL1R2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of IL5RA. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofIL7RA. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of IMMT. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of INPP5D. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of INSR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of INTS3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of INTU. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of IPO4. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of IPO8.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of IQGAP2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ISL2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ITFG1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ITGAL. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ITGB1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofITGB2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ITGB3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ITGB4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ITIH1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ITPR2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of IWS1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of JAG1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of JAK1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of JAK2. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofJMJD1C. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of KALRN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KATNAL2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KCNN2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KCNT2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA0256. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA0528. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA0564. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA0586. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1033. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1166. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1219. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1409. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1622. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1787. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF15. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF16B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF3B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF5A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF5B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF9. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of KIN. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of KIR2DL5B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of KIR3DL2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of KIR3DL3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of KLF12. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of KLF3. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofKLFIL20. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of KLK12. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KLKB1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KPNA5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KRAS. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of KREMEN1. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of KRIT1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of KRT5. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofKRTCAP2. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of L1CAM. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of L3MBTL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of L3MBTL2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LACE1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LAMA 1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LAMA2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LAMA3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LAMB1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LARP7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LDLR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of LENG1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LGALS3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LGMN. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of LHCGR. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofLHX6. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of LIMCH1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LIMK2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LMBRD1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LMBRD2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LMLN. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of LMNA. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LMO2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of LOC389634. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of LOC390110. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of LPA. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofLPCAT2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of LPL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LRP4. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of LRPPRC. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LRRC19. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LRRC42. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LRRK2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of LRWD1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofLUM. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of LVRN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LYN. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of LYST. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MADD. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MAGI1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofMAGT1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MALT1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MAP2K1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MAP4K4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MAPK8IP3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MAPK9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MAPT. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MATN2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MCF2L2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MCM6. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MDGA2. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofMEGF10. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MEGF11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MEMO1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MET. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MGAM. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MGAT4A. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MGAT5. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MGC16169. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of MGC34774. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of MIB1. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of MIER2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MKKS. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MKL2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MLANA. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MLH1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MLL5. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of MLX.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MME. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MPDZ. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MPI. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MRAP2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MRPL11. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofMRPL39. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MRPS28. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MRPS35. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MS4A13. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MSH2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MSMB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MST1R. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MTDH. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of MTF2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MTHFR. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MTIF2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MUC2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MUT. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MVK. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MYB. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofMYCBP2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MYH2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MYO19. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MYO3A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MYO9B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MYOM2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MYOM3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NAG. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NARG1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NARG2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NCOA1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofNDC80. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of NDFIP2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NEB. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NEDD4. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NEK1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NEK11. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofNEK5. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of NF1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NF2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NFE2L2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NFIA. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NFIX. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofNFKBIL2. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of NFRKB. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NKAIN2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NKAP. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NLRC3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NLRC5. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NLRP13. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofNLRP7. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of NLRP8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NME7. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NOL10. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NOS1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NOS2A. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofNOTCH1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of NPM1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NR1H4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NR4A3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NRXN1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NSMAF. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NSMCE2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NT5C. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NT5C3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NUBP1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NUBPL. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofNUDT5. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of NUMA 1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NUP160. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NUP88. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NUP98. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NUPL1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of OAT. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of OBFC2A. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of OBFC2B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of OLIG2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of OPA1. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of OPN4.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of OPTN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of OSBPL11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of OSBPL8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of OSGEPL1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of OTC. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of OXT. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PADI4. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PAH. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of PAN2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PAPOLG. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PARD3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PARVB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PAWR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PBGD. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PBRM1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PCBP4. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPCCA. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PCNX. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PCOTH. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PDCD4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PDE10A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PDE8B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PDH1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PDIA3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PDK4. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PDLIM5. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPDS5A. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PDS5B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PDXK. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PDZRN3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PELI2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PGK1. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of PGM2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PHACTR4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PHEX. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PHKB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PHLDB2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PHTF1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PIAS1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPIGF. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PIGN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PIGT. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PIK3C2G. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PIK3CG. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PIK3R1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PIP5K1A. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PITRM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PIWIL3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PKD1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PKD2. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofPKHD1L1. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of PKIB. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PKLR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PKM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PKM2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PLCB1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPLCB4. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PLCG1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PLD1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PLEKHA5. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PLEKHA7. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PLEKHM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PLKR. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PLXNC1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPMFBP 1. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of POLN. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of POLR3D. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of POMT2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of POSTN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPFIA2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPP1R12A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPP3CB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPP4C. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPP4R1L. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPP4R2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRAME. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRC1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PRDM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PRIM1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PRIM2. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPRKAR1A. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of PRKCA. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRKG1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRMT7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PROC. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PROCR. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PRODH. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PROSC. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPROX1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PRPF40B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRPF4B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRRG2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRUNE2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PSD3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PSEN1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PSMAL. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PTCH1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPTEN. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PTK2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTK2B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPN11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPN22. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPN3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPN4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPRD. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPRK. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPRM. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPRN2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPRT. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PUS10. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PVRL2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PYGM. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of QRSL1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RAB11FIP2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RAB23. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of RALBP1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofRALGDS. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of RB1CC1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RBL2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of RBM39. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RBM45. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of REC8. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of RFC4.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of RFT1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RFTN1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RHPN2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RIF1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of RLN3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RMND5B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RNF11. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of RNF32. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofRNFT1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of RNGTT. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ROCK1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ROCK2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RP1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of RP11-265F1. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RP13-36C9. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RP6KA3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RPAP3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of RPGR. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of RPN1.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of RPS6KA6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RRM1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of RRP1B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RSK2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of RTEL1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofRTF1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of RUFY1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RYR3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SAAL1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SAE 1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SBCAD. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofSCN11A. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SCN1A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCN2A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCN3A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCN4A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCN5A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCN8A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCNA. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SCO1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SCYL3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SDK1. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of SDK2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SEC24A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SEC24D. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SEC31A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SEL1L. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SENP3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SENP6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SENP7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SERPINA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SETD3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SETD4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SEZ6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SFRS12. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SGCE. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SGOL2. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofSGPL1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SH2D1A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SH3BGRL2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SH3PXD2A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SH3PXD2B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SH3RF2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SH3TC2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SIPA1L2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SIPA1L3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SIVA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SKAP1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SKIV2L2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC12A3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC13A1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC22A17. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC25A14. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC28A3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC38A1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC38A4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC39A10. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC4A2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC6A11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC6A13. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC6A6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC6A8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SMARCA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SMARCA5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SMC5. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SMN2. For example, the SMSM compoundsand methods of their use described herein can modulate splicing of exon7 of a pre-mRNA of SMN2. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of SMTN. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofSNCAIP. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SNRK. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SNRP70. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SNX6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SOD1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SPAG9. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SPATA13. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofSPATA4. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SPATS1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SPECC1L. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SPINK5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SPP2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SPTA1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SRP72. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SSX3. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of SSX5.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SSX9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STAG1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STAMBPL1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STARD6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STATE. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STK17B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STX3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of STXBP1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SUCLG2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SULF2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SUPT16H. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofSUPT6H. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SV2C. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SYCP1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SYCP2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SYT6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SYTL5. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TAF2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TBC1D26. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTBC1D29. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of TBC1D3G. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TBC1D8B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TBCEL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TBK1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TBPL1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TCEB3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TCF12. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTCP11L2. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of TDRD3. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TEAD1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TECTB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TEK. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TET2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TFRC. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TG. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of TGM7.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of TGS1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of THOC2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TIAL1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TIAM2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TIMM50. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TLK2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TM4SF20. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TM6SF1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TMEM156. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TMEM194A. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TMEM27. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TMEM77. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TMF1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TMPRSS6. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTNFRSF10A. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of TNFRSF10B.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of TNFRSF8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TNK2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TNKS. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TNKS2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TOM 1L1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTOM1L2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of TOP2B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TP53. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TP53BP2. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TP53I3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TP53INP1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TP63. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TRAF3IP3. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of TRAPPC2. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTRIM44. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of TRIM65. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TRIML1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TRIML2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TRPM3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TRPM5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TRPM7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TSC1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TSC2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TSHB. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TSPAN7. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTTC17. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of TTLL5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TTLL9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TTN. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TTPAL. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TTR. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TUSC3. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTXNDC10. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of UBE3A. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of UCK1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of UGT1A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of UHRF1BP1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of UNC45B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of UNC5C. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of USH2A. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofUSP1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of USP38. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of USP39. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of USP6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of UTP15. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of UTP18. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of UTP20. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofUTRN. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of UTX. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of UTY. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of UVRAG. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of UXT. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of VAPA. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of VPS29.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of VPS35. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of VPS39. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of VTI1A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of VTI1B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of VWA3B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDFY2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDR16. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDR17. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDR26. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDR44. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDR67. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDTC1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WRNIP1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WWC3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of XRN1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of XRN2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of XX-FW88277. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of YARS. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of YGM.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ZBTB20. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZC3H7A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZC3HAV1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZC3HC1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZFYVE1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF114. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF169. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF326. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF365. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF37A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF618. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZWINT.

In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing, such as alternative splicing ofa polynucleotide encoded by MAPT gene. In some embodiments, alternativesplicing of the MAPT pre-mRNA may lead to the expression of 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 isoforms of the tau protein. In some embodiments,alternative splicing of the MAPT pre-mRNA may lead to the expression of6 isoforms of the tau protein. In some embodiments, the 6 isoforms oftau include 3 four-repeat (4R) isoforms and 3 three-repeat (3R) isoformsof the tau protein. In the 3R tau isoforms exon 10 is excluded from thesplice variants. For example, a 3R tau isoform in which exon 10 isexcluded may include exon 2 and/or exon 3. In the 4R tau isoforms exon10 is included in the splice variants. For example, a 4R tau isoform inwhich exon 10 is included may include exon 2 and/or exon 3. Theinclusion or exclusion of exon 10 may depend on alternative splicingevents in a stem loop occurring at the exon 10 intron 10 junction. Insome embodiments, a mutation occurring at the 5′ss results in inclusionof exon 10 in an mRNA encoding the tau protein. In some embodiments, amutation in an ISS region of the stem loop results in exclusion of exon10 from the mRNA encoding the tau protein. In some embodiments, amutation at the 5′ss destabilizes the stem loop, thereby decreasing exon10 inclusion in the mRNA of tau. In some embodiments, a mutation at the5′ss inhibits binding of a spliceosome component to the pre-mRNA,thereby decreasing exon 10 inclusion in the mRNA of tau. In someembodiments, a mutation at the ISS region of the stem loop inhibitsbinding of a spliceosome component to the pre-mRNA, thereby increasingexon 10 inclusion in the mRNA of tau.

The ratio of 3R to 4R tau isoforms may contribute to a number ofconditions or diseases. In some embodiments, a subject without acondition or disease has a 3R to 4R ratio of 1:1. In some embodiments, asubject with a condition or disease described herein has a 3R to 4Rratio of about 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.5, 1:3, 1:3.5, 1:4,1:4.5 or 1:5. In some embodiments, a subject with a condition or diseasedescribed herein has a 3R to 4R ratio from about 1:1 to about 1:1.1,about 1:1 to about 1:1.2, about 1:1 to about 1:1.3, about 1:1 to about1:1.4, about 1:1 to about 1:1.5, about 1:1 to about 1:1.6, about 1:1 toabout 1:1.8, about 1:1 to about 1:2, about 1:1 to about 1:3, about 1:1to about 1:3.5, about 1:1 to about 1:4, about 1:1 to about 1:4.5, about1:1 to about 1:5, 1:2 to about 1:3, about 1:2 to about 1:4, about 1:2 toabout 1:5, about 1:3 to about 1:4, about 1:3 to about 1:5, or about 1:4to about 1:5. In some embodiments, a subject with a condition or diseasedescribed herein has a 4R to 3R ratio of about 1:1.2, 1:1.4, 1:1.6,1:1.8, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5. In some embodiments, asubject with a condition or disease described herein has a 4R to 3Rratio from about 1:1 to about 1:1.1, about 1:1 to about 1:1.2, about 1:1to about 1:1.3, about 1:1 to about 1:1.4, about 1:1 to about 1:1.5,about 1:1 to about 1:1.6, about 1:1 to about 1:1.8, about 1:1 to about1:2, about 1:1 to about 1:3, about 1:1 to about 1:3.5, about 1:1 toabout 1:4, about 1:1 to about 1:4.5, about 1:1 to about 1:5, 1:2 toabout 1:3, about 1:2 to about 1:4, about 1:2 to about 1:5, about 1:3 toabout 1:4, about 1:3 to about 1:5, or about 1:4 to about 1:5.

In some aspects, the SMSM compounds are used to modulate alternativesplicing of tau pre-mRNA. In some embodiments, the SMSM compound bindsto the stem loop of exon 10 of the tau pre-mRNA, reducing bindingaffinity of a spliceosome component to the 5′ss, thereby increasingexclusion of exon 10 in the mRNA of tau and increasing the ratio of3R:4R tau isoforms. In some embodiments, the SMSM compound binds to thestem loop of exon 10 of the tau pre-mRNA, increasing binding affinity ofa spliceosome component to the 5′ss, thereby increasing inclusion ofexon 10 in the mRNA of tau and decreasing the ratio of 3R:4R tauisoforms. In some embodiments, the SMSM compound binds to the stem loopof exon 10 of the tau pre-mRNA, reducing binding affinity of aspliceosome component to the ISS region, thereby increasing inclusion ofexon 10 in the mRNA of tau and decreasing the ratio of 3R:4R tauisoforms. In some embodiments, the SMSM compound binds to the stem loopof exon 10 of the tau pre-mRNA, increasing binding affinity of aspliceosome component to the ISS region, thereby reducing inclusion ofexon 10 in the mRNA of tau and increasing the ratio of 3R:4R tauisoforms. In some embodiments, the SMSM compound restores the ratio of3R:4R to 1:1. In some embodiments, the SMSM compound alters the ratiofrom 3R>4R to 4R>3R. In some embodiments, the SMSM compound alters theratio from 3R<4R to 4R<3R. In some embodiments, the SMSM compound bindsto the stem loop of exon 10 of the tau pre-mRNA, increasing thethermodynamic stability of the stem loop, thereby reducing inclusion ofexon 10 in the mRNA of tau and increasing the ratio of 3R:4R tauisoforms. In some embodiments, the SMSM compound binds to the stem loopof exon 10 of the tau pre-mRNA, decreasing the thermodynamic stabilityof the stem loop, thereby increasing inclusion of exon 10 in the mRNA oftau and decreasing the ratio of 3R:4R tau isoforms.

Mutations and/or aberrant secondary or tertiary RNA structures incis-acting elements of splicing can alter splicing patterns. Mutationsand/or aberrant secondary or tertiary RNA structures can be found incore consensus sequences, including 5′ ss, 3′ ss, and BP regions, orother regulatory elements, including ESEs, ESSs, ISEs, and ISSs.Mutations in cis-acting elements can result in multiple diseases.Exemplary diseases are described below. The present disclosure providessplice modulating compounds and methods that target pre-mRNA containingone or more mutations and/or aberrant secondary or tertiary RNAstructures in cis-acting elements. In some embodiments, the presentdisclosure provides methods and small molecule binding agents thattarget pre-mRNA containing one or more mutations and/or aberrantsecondary or tertiary RNA structures in splice sites or BP regions. Insome embodiments, the present disclosure provides methods and smallmolecule binding agents that target pre-mRNA containing one or moremutations and/or aberrant secondary or tertiary RNA structures in otherregulatory elements, for example, ESEs, ESSs, ISEs, and ISSs.

In some embodiments, splicing at a splice site sequence of apolynucleotide of primary cells is modulated. In some embodiments,splicing at a splice site sequence of a polynucleotide of cells of atumor is modulated. In some embodiments, the SMSM modulates splicing ata cryptic splice site sequence. In some embodiments, an SMSM modulatessplicing of splice site of a polynucleotide. In some embodiments,wherein the polynucleotide is transcribed from the gene. In someembodiments, SMSM modulates exon inclusion in the polynucleotide andsplicing of the splice site sequence. In some embodiments, the SMSMmodulates pseudoexons inclusion in the polynucleotide and splicing ofthe splice site sequence. In some embodiments, the SMSM modulatessplicing at a cryptic splice site sequence of a polynucleotide.

In some embodiments, an SMSM modulates splicing by preventing,inhibiting or reducing splicing of the polynucleotide. In someembodiments, an SMSM modulates splicing by preventing, inhibiting orreducing splicing at the splice site sequence. In some embodiments, anSMSM decreases affinity of a splicing complex component to thepolynucleotide. In some embodiments, an SMSM decreases affinity of asplicing complex component to the polynucleotide at the splice sitesequence, upstream of the splice site sequence or downstream of thesplice site sequence. In some embodiments, an SMSM inhibits or reduces arate of catalysis of splicing of the polynucleotide. In someembodiments, an SMSM inhibits or reduces a rate of catalysis of splicingof the polynucleotide at the splice site sequence. In some embodiments,an SMSM increases steric hindrance between a splicing complex componentand the polynucleotide. In some embodiments, an SMSM increases sterichindrance between a splicing complex component and the polynucleotide atthe splice site sequence, upstream of the splice site sequence ordownstream of the splice site sequence. In some embodiments, an SMSMincreases steric hindrance between a first splicing complex componentand a second splicing complex component. In some embodiments, an SMSMprevents, inhibits, disrupts or reduces binding of a first splicingcomplex component and a second splicing complex component.

In some embodiments, an SMSM decreases affinity of a first splicingcomplex component to a second splicing complex component. In someembodiments, an SMSM prevents, inhibits, disrupts or reduces binding ofa splicing complex component to the polynucleotide. In some embodiments,an SMSM prevents, inhibits, disrupts or reduces binding of a splicingcomplex component to the polynucleotide at the splice site sequence,upstream of the splice site sequence or downstream of the splice sitesequence.

In some embodiments, an SMSM modulates splicing by promoting orincreasing splicing of the polynucleotide. In some embodiments, an SMSMmodulates splicing by promoting or increasing splicing the splice sitesequence. In some embodiments, an SMSM increases affinity of a splicingcomplex component to the polynucleotide. In some embodiments, an SMSMincreases affinity of a splicing complex component to the polynucleotideat the splice site sequence, upstream of the splice site sequence ordownstream of the splice site sequence. In some embodiments, an SMSMincreases a rate of catalysis of splicing of the polynucleotide. In someembodiments, an SMSM increases a rate of catalysis of splicing of thepolynucleotide at the splice site sequence. In some embodiments, an SMSMdecreases or reduces steric hindrance between a splicing complexcomponent and the polynucleotide. In some embodiments, an SMSM decreasessteric hindrance between a splicing complex component and thepolynucleotide at the splice site sequence, 1-1000 nucleobases basesupstream of the splice site sequence or 1-1000 nucleobases downstream ofthe splice site sequence. In some embodiments, an SMSM decreases orreduces steric hindrance between a first splicing complex component anda second splicing complex component. In some embodiments, an SMSMpromotes or increases binding of a first splicing complex component anda second splicing complex component. In some embodiments, an SMSMincreases affinity of a first splicing complex component to a secondsplicing complex component. In some embodiments, an SMSM promotes orincreases binding of a splicing complex component to the polynucleotide.In some embodiments, an SMSM promotes or increases binding of a splicingcomplex component to the polynucleotide at the splice site sequence,1-1000 nucleobases upstream of the splice site sequence or 1-1000nucleobases downstream of the splice site sequence. In some embodiments,an SMSM binds to a splicing complex component, the polynucleotide, or acombination thereof. In some embodiments, an SMSM binds to thepolynucleotide at the splice site sequence, 1-1000 nucleobases upstreamof the splice site sequence or 1-1000 nucleobases downstream of thesplice site sequence. In some embodiments, an SMSM structurallymodulates a splicing complex component, the polynucleotide, or both. Insome embodiments, an SMSM promotes or increases steric hindrance, stericshielding, steric attraction, chain crossing, steric repulsions, stericinhibition of resonance, steric inhibition of protonation, or acombination thereof of the polynucleotide, a splicing complex componentor a combination thereof. In some embodiments, binding of an SMSM to apolynucleotide or a splicing complex component decreases conformationalstability of a splice site sequence. In some embodiments, binding of anSMSM to a polynucleotide increases conformational stability of a splicesite sequence.

In some embodiments, an SMSM modulates exon skipping of a targetpolynucleotide, such as a pre-mRNA. For example, an SMSM can inhibitexon skipping of a target polynucleotide, such as a pre-mRNA. Forexample, an SMSM can promote exon skipping of a target polynucleotide,such as a pre-mRNA. In some embodiments, an SMSM modulates splicing at asplice site sequence of a polynucleotide in a cell of a subject with adisease or condition associated with exon skipping of thepolynucleotide, such as a pre-mRNA. In some embodiments, an SMSMmodulates splicing at a splice site sequence of a polynucleotide in acell of a subject with a disease or condition associated with aberrantexon skipping of the polynucleotide, such as a pre-mRNA.

In some embodiments, an SMSM modulates exon inclusion of a targetpolynucleotide, such as a pre-mRNA. For example, an SMSM can inhibitexon inclusion of a target polynucleotide, such as a pre-mRNA. Forexample, an SMSM can promote exon inclusion of a target polynucleotide,such as a pre-mRNA. In some embodiments, an SMSM modulates splicing at asplice site sequence of a polynucleotide in a cell of a subject with adisease or condition associated with exon inclusion of thepolynucleotide, such as a pre-mRNA. In some embodiments, an SMSMmodulates splicing at a splice site sequence of a polynucleotide in acell of a subject with a disease or condition associated with aberrantexon inclusion of the polynucleotide, such as a pre-mRNA.

In some embodiments, an SMSM modulates nonsense mediated degradation(NMD) of a target polynucleotide, such as a pre-mRNA. For example, anSMSM can inhibit nonsense mediated degradation (NMD) of a targetpolynucleotide, such as a pre-mRNA or an mRNA. In some embodiments, anSMSM modulates splicing at a splice site sequence of a polynucleotide ina cell of a subject with a disease or condition associated with NMD ofthe polynucleotide, such as a pre-mRNA or an mRNA.

In some embodiments, an SMSM modulates intron inclusion of a targetpolynucleotide. For example, an SMSM can inhibit intron inclusion of atarget polynucleotide, such as a pre-mRNA. For example, an SMSM canpromote intron inclusion of a target polynucleotide, such as a pre-mRNA.In some embodiments, an SMSM modulates splicing at a splice sitesequence of a polynucleotide in a cell of a subject with a disease orcondition associated with intron inclusion of the polynucleotide. Insome embodiments, the SMSM modulates splicing at a splice site sequenceof a polynucleotide in a cell of a subject with a disease or conditionassociated with intron inclusion of the polynucleotide.

In some embodiments, an SMSM modulates splicing at splice site sequenceof a polynucleotide, such as a pre-mRNA, wherein the splice sitesequence comprises a sequence selected from the group consisting ofNGAgunvrn, NHAdddddn, NNBnnnnnn, and NHAddmhvk; wherein N or n is A, U,G or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is aor c; r is a or g; v is a, c or g; k is g or u.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence NNBgunnnn, NNBhunnnn, or NNBgvnnnn Insome embodiments, an SMSM modulates splicing of a splice site sequencecomprising a sequence NNBgurrrn, NNBguwwdn, NNBguvmvn, NNBguvbbn,NNBgukddn, NNBgubnbd, NNBhunngn, NNBhurmhd, or NNBgvdnvn; wherein N or nis A, U, G or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u;m is a or c; r is a or g; v is a, c or g; k is g or u.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2A, Table 2B, Table 2C or Table2D. In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence AAAauaagu, AAAguaagua (SEQ ID NO: 1),AAAguacau, AAAguaga, AAAguaug, AAAguaugu, AAAgugagug (SEQ ID NO: 2),AAAgugaguu (SEQ ID NO: 3), AACaugagga (SEQ ID NO: 4), AACguaagu,AACgugacu, AACgugauu, AAGaugagc, AAGauuugu, AAGgaugag, AAGgcaaaa,AAGgcaaggg (SEQ ID NO: 5), AAGgcaggga (SEQ ID NO: 6), AAGggaaaa,AAGguaugag (SEQ ID NO: 7), AAGguaaag, AAGguaaau, AAGguaaca, AAGguaacaug(SEQ ID NO: 8), AAGguaacu, AAGguaagcc (SEQ ID NO: 9), AAGguaagcg (SEQ IDNO: 10), AAGguaauaa (SEQ ID NO: 11), AAGguaaugu (SEQ ID NO: 12),AAGguaaugua (SEQ ID NO: 13), AAGguacag, AAGguacgg, AAGguacug, AAGguagacc(SEQ ID NO: 14), AAGguagag, AAGguagcg, AAGguagua, AAGguagug, AAGguauac,AAGguauau, AAGguauauu (SEQ ID NO: 15), AAGguauca, AAGguaucg, AAGguaucu,AAGguauga, AAGguaugg, AAGguaugu, AAGguauuu, AAGgucaag, AAGgucaau,AAGgucucu, AAGgucuggg (SEQ ID NO: 16), AAGgucugu, AAGgugaccuu (SEQ IDNO: 17), AAGgugagau (SEQ ID NO: 18), AAGgugaguc (SEQ ID NO: 19),AAGgugccu, AAGgugggcc (SEQ ID NO: 20), AAGgugggu, AAGguggua, AAGguguau,AAGgugucu, AAGgugugc, AAGgugugu, AAGguguua, AAGguuaag, AAGguuagc,AAGguuagug (SEQ ID NO: 21), AAGguuca, AAGguuuaa, AAGguuuau, AAGguuugg,AAGuuaagg, AAGuuaaua, AAGuuagga, AAUguaaau, AAUguaagc, AAUguaagg,AAUguaauu, AAUguaugu, AAUgugagu, AAUgugugu, ACAguaaau, ACAgugagg,ACAguuagu, ACAguuuga, ACCaugagu, ACCgugaguu (SEQ ID NO: 22), ACGauaagg,ACGcuaagc, ACGguagcu, ACGgugaac, ACGgugagug (SEQ ID NO: 23), ACUguaaau,ACUguaacu, ACUguauu, ACUgugagug (SEQ ID NO: 24), AGAguaag, AGAguaaga,AGAguaagg, AGAguaagu, AGAguagau, AGAguaggu, AGAgugaau, AGAgugagc,AGAgugagu, AGAgugcgu, AGCguaagg, AGCguaagu, AGCguacgu, AGCguaggu,AGCgugagu, AGGguaauga (SEQ ID NO: 25), AGGguagac, AGGguauau, AGGgugaau,AGGgugagg, AGGgugauc, AGGgugcaa, AGGgugucu, AGUguaagc, AGUguaagu,AGUgugagu, AGUgugaguac (SEQ ID NO: 26), AUAgucagu, AUAgugaau, AUCgguaaaa(SEQ ID NO: 27), AUCguuaga, AUGguaaaa, AUGguaacc, AUGguacau, AUGguaugu,AUGguauuu, AUGgucauu, AUGgugacc, AUUuuaagc, CAAGguaccu (SEQ ID NO: 28),CAAguaaac, CAAguaacu, CAAguaagc, CAAguaagg, CAAguaagua (SEQ ID NO: 29),CAAguaau, CAAguaugu, CAAguauuu, CAAgugaaa, CAAgugagu, CACgugagc,CACguuggu, CAGauaacu, CAGaugagg, CAGaugagu, CAGauuggu, CAGcugugu,CAGgcgagu, CAGgcuggu, CAGguaaggc (SEQ ID NO: 30), CAGguaaaa, CAGguaaag,CAGguaaccuc (SEQ ID NO: 31), CAGguaagac (SEQ ID NO: 32), CAGguaagc,CAGguaagu, CAGguaau, CAGguaaugc (SEQ ID NO: 33), CAGguaaugu (SEQ ID NO:34), CAGguacaa, CAGguacag, CAGguacagu (SEQ ID NO: 35), CAGguaccg,CAGguacug, CAGguagag, CAGguagcaa (SEQ ID NO: 36), CAGguaggagg (SEQ IDNO: 37), CAGguaggc, CAGguagguga (SEQ ID NO: 38), CAGguagua, CAGguagug,CAGguauag, CAGguauau, CAGguaucc, CAGguauga, CAGguaugg, CAGguaugu,CAGguauug, CAGgucaau, CAGgucagug (SEQ ID NO: 39), CAGgucuga, CAGgucugga(SEQ ID NO: 40), CAGgucuggu (SEQ ID NO: 41), CAGgucuuu, CAGgugacu,CAGgugagc, CAGgugaggg (SEQ ID NO: 42), CAGgugagugg (SEQ ID NO: 43),CAGgugaua, CAGgugcac, CAGgugcag, CAGgugcgc, CAGgugcug, CAGguggau,CAGgugggug (SEQ ID NO: 44), CAGgugua, CAGguguag, CAGguguau, CAGguguga,CAGgugugu, CAGguuaag, CAGguugau, CAGguugcu, CAGguuggc, CAGguuguc,CAGguuguu, CAGguuuagu (SEQ ID NO: 45), CAGguuugc, CAGguuugg, CAGuuuggu,CAUggaagac (SEQ ID NO: 46), CAUguaau, CAUguaauu, CAUguaggg, CAUguauuu,CCAguaaac, CCAgugaga, CCGguaacu, CCGgugaau, CCGgugacu, CCGgugagg,CCUauaagu, CCUaugagu, CCUguaaau, CCUguaagc, CCUguaauu, CCUgugaau,CCUgugauu, CGAguccgu, CGCauaagu, CGGguaau, CGGguauau, CGGguaugg,CGGgucauaauc (SEQ ID NO: 47), CGGgugggu, CGGguguau, CGGgugugu,CGUgugaau, CGUgugggu, CUGguauga, CUGgugaau, CUGgugaguc (SEQ ID NO: 48),CUGgugaguuc (SEQ ID NO: 49), CUGgugcau, CUGgugcuu, CUGguguga, CUGguuugu,CUGuuaag, CUGuugaga, GAAggaagu, GAAguaaac, GAAguaaau, GAAgucugg,GAAguggg, GAAgugugu, GAAuaaguu, GACaugagg, GAGaucugg, GAGaugagg,GAGCAGguaagcu (SEQ ID NO: 50), GAGcugcag, GAGgcaggu, GAGgcgugg,GAGgcuccc, GAGguggguuu (SEQ ID NO: 51), GAGguaaag, GAGguaaga, GAGguaagag(SEQ ID NO: 52), GAGguaagcg (SEQ ID NO: 53), GAGguaauac (SEQ ID NO: 54),GAGguaauau (SEQ ID NO: 55), GAGguaaugu (SEQ ID NO: 56), GAGguacaa,GAGguagga, GAGguauau, GAGguauga, GAGguaugg, GAGgucuggu (SEQ ID NO: 57),GAGgugaag, GAGgugagg, GAGgugca, GAGgugccu, GAGgugcggg (SEQ ID NO: 58),GAGgugcug, GAGguguac, GAGguguau, GAGgugugc, GAGgugugu, GAGuuaagu,GAUaugagu, GAUguaaau, GAUguaagu, GAUguaauu, GAUguaua, GAUgugacu,GAUgugagg, GAUgugauu, GCAguaaau, GCAguagga, GCAguuagu, GCGaugagu,GCGgagagu, GCGguaaaa, GCGguaauca (SEQ ID NO: 59), GCGgugacu, GCGgugagca(SEQ ID NO: 60), GCGgugagcu (SEQ ID NO: 61), GCGguggga, GCGguuagu,GCUguaaau, GCUguaacu, GCUguaauu, GGAguaag, GGAguaagg, GGAguaagu,GGAguaggu, GGAgugagu, GGAguuagu, GGCguaagu, GGCgucagu, GGGauaagu,GGGaugagu, GGGguaagug (SEQ ID NO: 62), GGGguaaau, GGGguaacu, GGGguacau,GGGgugacg, GGGgugagug (SEQ ID NO: 63), GGGgugcau, GGGguuggga (SEQ ID NO:64), GGUguaagu, GUAgugagu, GUGguaagu, GUGguaagug (SEQ ID NO: 65),GUGgugagc, GUGgugagu, GUGgugauc, GUGguugua, GUUauaagu, GUUCUCAgugug (SEQID NO: 66), GUUguaaau, GUUuugguga (SEQ ID NO: 67), uAGCAGguaagca (SEQ IDNO: 68), uGGguaccug (SEQ ID NO: 69), UAGaugcgu, UAGguaaag, UAGguaccc,UAGguaggu, UAGguauau, UAGguauc, UAGguauga, UAGguauug, UAGgucaga,UAGgugcau, UAGguguau, UCAguaaac, UCAguaaau, UCAguaagu, UCAgugauu,UCAgugug, UCCgugaau, UCCgugacu, UCCgugagc, UCUguaaau, UGAgugaau,UGGauaagg, UGGguaaag, UGGguacca, UGGguaugc, UGGguggau, UGGguggggg (SEQID NO: 70), UGGgugggug (SEQ ID NO: 71), UGGgugugg, UGGguuagu, UGUgcaagu,UGUguaaau, UGUguacau, UUAguaaau, UUCauaagu, UUGguaaag, UUGguaaca,UUGguacau, UUGguagau, UUGgugaau, UUGgugagc, UUUauaagc or UUUgugagc.

ABCA4, ABCA9, ABCB1, ABCB5, ABCC9, ABCD1, ACADL, ACADM, ACADSB, ACSS2,ACTG2, ADA, ADAL, ADAM10, ADAM15, ADAM22, ADAM32, ADAMTS12, ADAMTS13,ADAMTS20, ADAMTS6, ADAMTS9, ADCY10, ADCY3, ADCY8, ADRBK2, AFP, AGL, AGT,AHCTF1, AKAP10, AKAP3, AKNA, ALAS1, ALB, ALDH3A2, ALG6, ALS2CL, AMBRA1,ANGPTL3, ANK3, ANTXR2, ANXA10, ANXA11, AP2A2, AP4E1, APC, APOA1, APOB,APOC3, APOH, AR, ARFGEF1, ARFGEF2, ARHGAP1, ARHGAP18, ARHGAP26, ARHGAP8,ARHGEF18, ARHGEF2, ARPC3, ARS2, ASH1L, ASNSD1, ASPM, ATAD5, ATG16L2,ATG4A, ATM, ATP11C, ATP13A5, ATP6V1G3, ATP7A, ATP7B, ATR, ATXN2, ATXN3,B2M, B4GALNT3, BBOX1, BBS4, BCL2-like 11 (BIM), BCS1L, BMP2K, BMPR2,BRCA1, BRCA2, BRCC3, BRSK1, BRSK2, BTAF1, BTK, C10orf137, C11orf30,C11orf65, C11orf70, C12orf51, C13orf1, C13orf15, C14orf101, C14orf118,C15orf29, C15orf42, C15orf60, C16orf33, C16orf38, C16orf48, C18orf8,C19orf42, C1orf107, C1orf114, C1orf130, C1orf149, C1orf27, C1orf71,C1orf87, C1orf94, C1R, C20orf74, C21orf70, C2orf55, C3, C3orf23,C4orf18, C4orf29, C5orf34, C6orf118, C8B, C8orf33, C9orf114, C9orf43,C9orf86, C9orf98, CA11, CAB39, CACHD1, CACNA1B, CACNA1C, CACNA1G,CACNA1H, CACNA2D1, CALCA, CALCOCO2, CAMK1D, CAMKK1, CAPN3, CAPN9, CAPSL,CARKD, CAT, CBX1, CBX3, CCDC102B, CCDC11, CCDC131, CCDC146, CCDC15,CCDC18, CCDC5, CCDC81, CD1B, CD33, CD4, CD46, CDC14A, CDC16, CDC2L5,CDC42BPB, CDCA8, CDH1, CDH10, CDH11, CDH23, CDH24, CDH8, CDH9, CDK5RAP2,CDK6, CDK8, CEL, CELSR3, CENPI, CENTB2, CENTG2, CEP110, CEP170, CEP192,CETP, CFB, CFH, CFTR, CGN, CGNL1, CHAF1A, CHD9, CHIC2, CHL1, CHM, CHN1,CLCN1, CLEC16A, CLIC2, CLINT1, CLK1, CLPB, CLPTM1, CMIP, CMYA5, CNGA3,CNOT1, CNOT7, CNTN6, COG3, COL11A1, COL11A2, COL12A1, COL14A1, COL15A1,COL17A1, COL19A1, COL1A1, COL1A2, COL22A1, COL24A1, COL25A1, COL29A1,COL2A1, COL3A1, COL4A1, COL4A2, COL4A5, COL4A6, COL5A2, COL6A1, COL7A1,COL9A1, COL9A2, COLQ, COMTD1, COPA, COPB2, COPS7B, COPZ2, CPSF2, CPXM2,CR1, CREBBP, CRKRS, CRYZ, CSE1L, CSTB, CSTF3, CT45-6, CUBN, CUL4B, CUL5,CXorf41, CYBB, CYFIP2, CYP17, CYP19, CYP24A1, CYP27A1, CYP3A4, CYP3A43,CYP3A5, CYP4F2, CYP4F3, DAZ2, DCBLD1, DCC, DCTN3, DCUN1D4, DDA1, DDEF1,DDX1, DDX24, DDX4, DENND2D, DEPDC2, DES, DGAT2, DHFR, DHRS7, DHRS9,DIP2A, DMD, DMTF1, DNAH3, DNAH8, DNAI1, DNAJA4, DNAJC13, DNAJC7,DNTTIP2, DOCK10, DOCK11, DOCK4, DPP3, DPP4, DPY19L2P2, DSCC1, DUX4,DVL3, DYNC1H1, DYSF, ECM2, EDEM3, EFCAB3, EFCAB4B, EFNA4, EFTUD2, EGFR,EIF3A, ELA1, ELA2A, EMCN, EMD, EML5, ENPP3, EPB41L5, EPHA3, EPHA4,EPHB1, EPHB2, EPHB3, EPS15, ERBB4, ERCC1, ERCC8, ERGIC3, ERMN, ERMP1,ERN1, ERN2, ETS2, ETV4, EVC2, EXO1, EXOC4, F11, F13A1, F3, F5, F7, F8,FAH, FAM134A, FAM13A1, FAM13B1, FAM13C1, FAM161A, FAM176B, FAM184A,FAM19A1, FAM20A, FAM23B, FAM65C, FANCA, FANCC, FANCG, FANCM, FANK1,FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGBP, FECH, FEZ2, FGA, FGD6,FGFR1OP, FGFR1OP2, FGFR2, FGG, FGR, FIX, FKBP3, FLJ35848, FLJ36070,FLNA, FN1, FNBP1L, FOLH1, FOXM1, FRAS1, FUT9, FZD3, FZD6, GAB1, GALC,GALNT3, GAPDH, GART, GAS2L3, GBA, GBGT1, GCG, GCGR, GCK, GFM1, GH1, GHR,GHV, GJA1, GLA, GLT8D1, GNAS, GNB5, GOLGB1, GOLT1A, GOLT1B, GPATCH1,GPR158, GPR160, GRAMD3, GRHPR, GRIA1, GRIA3, GRIA4, GRIN2B, GRM3, GRM4,GRN, GSDMB, GSTCD, GSTO2, GTPBP4, HADHA, HBA2, HBB, HCK, HDAC3, HDAC5,HDX, HEPACAM2, HERC1, HEXA, HEXB, HIPK3, HLA-DPB1, HLA-G, HLCS, HLTF,HMBS, HMGCL, HNF1A, HNRNPH1, HP1BP3, HPGD, HPRT1, HPRT2, HSF2BP, HSF4,HSPA9, HSPG2, HTT, HXA, ICA1, IDH1, IDS, IFI44L, IKBKAP, IL1R2, IL5RA,IL7RA, IMMT, INPP5D, INSR, INTS3, INTU, IPO4, IPO8, IQGAP2, ISL2, ITFG1,ITGAL, ITGB1, ITGB2, ITGB3, ITGB4, ITIH1, ITPR2, IWS1, JAG1, JAK1, JAK2,JMJD1C, KALRN, KATNAL2, KCNN2, KCNT2, KIAA0256, KIAA0528, KIAA0564,KIAA0586, KIAA1033, KIAA1166, KIAA1219, KIAA1409, KIAA1622, KIAA1787,KIF15, KIF16B, KIF3B, KIF5A, KIF5B, KIF9, KIN, KIR2DL5B, KIR3DL2,KIR3DL3, KLF12, KLF3, KLHL20, KLK12, KLKB1, KPNA5, KRAS, KREMEN1, KRIT1,KRT5, KRTCAP2, L1CAM, L3MBTL, L3MBTL2, LACE1, LAMA1, LAMA2, LAMA3,LAMB1, LARP7, LDLR, LENG1, LGALS3, LGMN, LHCGR, LHX6, LIMCH1, LIMK2,LMBRD1, LMBRD2, LMLN, LMNA, LMO2, LOC389634, LOC390110, LPA, LPCAT2,LPL, LRP4, LRPPRC, LRRC19, LRRC42, LRRK2, LRWD1, LUM, LVRN, LYN, LYST,MADD, MAGI1, MAGT1, MALT1, MAP2K1, MAP4K4, MAPK8IP3, MAPK9, MAPT, MATN2,MCF2L2, MCM6, MDGA2, MEGF10, MEGF11, MEMO1, MET, MGAM, MGAT4A, MGAT5,MGC16169, MGC34774, MIB1, MIER2, MKKS, MKL2, MLANA, MLH1, MLL5, MLX,MME, MPDZ, MPI, MRAP2, MRPL11, MRPL39, MRPS28, MRPS35, MS4A13, MSH2,MSMB, MST1R, MTDH, MTF2, MTHFR, MTIF2, MUC2, MUT, MVK, MYB, MYCBP2,MYH2, MYO19, MYO3A, MYO9B, MYOM2, MYOM3, NAG, NARG1, NARG2, NCOA1,NDC80, NDFIP2, NEB, NEDD4, NEK1, NEK11, NEK5, NF1, NF2, NFE2L2, NFIA,NFIX, NFKBIL2, NFRKB, NKAIN2, NKAP, NLRC3, NLRC5, NLRP13, NLRP7, NLRP8,NME7, NOL10, NOS1, NOS2A, NOTCH1, NPM1, NR1H4, NR4A3, NRXN1, NSMAF,NSMCE2, NT5C, NT5C3, NUBP1, NUBPL, NUDT5, NUMA1, NUP160, NUP88, NUP98,NUPL1, OAT, OBFC2A, OBFC2B, OLIG2, OPA1, OPN4, OPTN, OSBPL11, OSBPL8,OSGEPL1, OTC, OXT, PADI4, PAH, PAN2, PAPOLG, PARD3, PARVB, PAWR, PBGD,PBRM1, PCBP4, PCCA, PCNX, PCOTH, PDCD4, PDE10A, PDE8B, PDH1, PDIA3,PDK4, PDLIM5, PDS5A, PDS5B, PDXK, PDZRN3, PELI2, PGK1, PGM2, PHACTR4,PHEX, PHKB, PHLDB2, PHTF1, PIAS1, PIGF, PIGN, PIGT, PIK3C2G, PIK3CG,PIK3R1, PIP5K1A, PITRM1, PIWIL3, PKD1, PKD2, PKHD1L1, PKIB, PKLR, PKM1,PKM2, PLCB1, PLCB4, PLCG1, PLD1, PLEKHA5, PLEKHA7, PLEKHM1, PLKR,PLXNC1, PMFBP1, POLN, POLR3D, POMT2, POSTN, PPFIA2, PPP1R12A, PPP3CB,PPP4C, PPP4R1L, PPP4R2, PRAME, PRC1, PRDM1, PRIM1, PRIM2, PRKAR1A,PRKCA, PRKG1, PRMT7, PROC, PROCR, PRODH, PROSC, PROX1, PRPF40B, PRPF4B,PRRG2, PRUNE2, PSD3, PSEN1, PSMAL, PTCH1, PTEN, PTK2, PTK2B, PTPN11,PTPN22, PTPN3, PTPN4, PTPRD, PTPRK, PTPRM, PTPRN2, PTPRT, PUS10, PVRL2,PYGM, QRSL1, RAB11FIP2, RAB23, RALBP1, RALGDS, RB1CC1, RBL2, RBM39,RBM45, REC8, RFC4, RFT1, RFTN1, RHPN2, RIF1, RLN3, RMND5B, RNF11, RNF32,RNFT1, RNGTT, ROCK1, ROCK2, RP1, RP11-265F1, RP13-36C9, RP6KA3, RPAP3,RPGR, RPN1, RPS6KA6, RRM1, RRP1B, RSK2, RTEL1, RTF1, RUFY1, RYR3, SAAL1,SAE1, SBCAD, SCN11A, SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCNA,SCO1, SCYL3, SDK1, SDK2, SEC24A, SEC24D, SEC31A, SEL1L, SENP3, SENP6,SENP7, SERPINA1, SETD3, SETD4, SEZ6, SFRS12, SGCE, SGOL2, SGPL1, SH2D1A,SH3BGRL2, SH3PXD2A, SH3PXD2B, SH3RF2, SH3TC2, SIPA1L2, SIPA1L3, SIVA1,SKAP1, SKIV2L2, SLC12A3, SLC13A1, SLC22A17, SLC25A14, SLC28A3, SLC38A1,SLC38A4, SLC39A10, SLC4A2, SLC6A11, SLC6A13, SLC6A6, SLC6A8, SMARCA1,SMARCA5, SMC5, SMN2, SMTN, SNCAIP, SNRK, SNRP70, SNX6, SOD1, SPAG9,SPATA13, SPATA4, SPATS1, SPECC1L, SPINK5, SPP2, SPTA1, SRP72, SSX3,SSX5, SSX9, STAG1, STAMBPL1, STARD6, STAT6, STK17B, STX3, STXBP1,SUCLG2, SULF2, SUPT16H, SUPT6H, SV2C, SYCP1, SYCP2, SYT6, SYTL5, TAF2,TBC1D26, TBC1D29, TBC1D3G, TBC1D8B, TBCEL, TBK1, TBPL1, TCEB3, TCF12,TCP11L2, TDRD3, TEAD1, TECTB, TEK, TET2, TFRC, TG, TGM7, TGS1, THOC2,TIAL1, TIAM2, TIMM50, TLK2, TM4SF20, TM6SF1, TMEM156, TMEM194A, TMEM27,TMEM77, TMF1, TMPRSS6, TNFRSF10A, TNFRSF10B, TNFRSF8, TNK2, TNKS, TNKS2,TOM1L1, TOM1L2, TOP2B, TP53, TP53BP2, TP53I3, TP53INP1, TP63, IRAF3IP3,TRAPPC2, TRIM44, TRIM65, TRIML1, TRIML2, TRPM3, TRPM5, TRPM7, TSC1,TSC2, TSHB, TSPAN7, TTC17, TTLL5, TTLL9, TTN, TTPAL, TTR, TUSC3,TXNDC10, UBE3A, UCK1, UGT1A1, UHRF1BP1, UNC45B, UNC5C, USH2A, USP1,USP38, USP39, USP6, UTP15, UTP18, UTP20, UTRN, UTX, UTY, UVRAG, UXT,VAPA, VPS29, VPS35, VPS39, VTI1A, VTI1B, VWA3B, WDFY2, WDR16, WDR17,WDR26, WDR44, WDR67, WDTC1, WRNIP1, WWC3, XRN1, XRN2, XX-FW88277, YARS,YGM, ZBTB20, ZC3H7A, ZC3HAV1, ZC3HC1, ZFYVE1, ZNF114, ZNF169, ZNF326,ZNF365, ZNF37A, ZNF618 or a ZWINT

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2A. In some embodiments, an SMSMmodulates splicing of a splice site sequence comprising a sequenceAAAauaagu, AAAguaagua (SEQ ID NO: 1), AAAguacau, AAAguaga, AAAguaug,AAAguaugu, AAAgugagug (SEQ ID NO: 2), AAAgugaguu (SEQ ID NO: 3),AACaugagga (SEQ ID NO: 4), AACguaagu, AACgugacu, AACgugauu, AAGaugagc,AAGauuugu, AAGgaugag, AAGgcaaaa, AAGgcaaggg (SEQ ID NO: 5), AAGgcaggga(SEQ ID NO: 6), AAGggaaaa, AAGgtatgag (SEQ ID NO: 72), AAGguaaag,AAGguaaau, AAGguaaca, AAGguaacaug (SEQ ID NO: 8), AAGguaacu, AAGguaagcc(SEQ ID NO: 9), AAGguaagcg (SEQ ID NO: 10), AAGguaauaa (SEQ ID NO: 11),AAGguaaugu (SEQ ID NO: 12), AAGguaaugua (SEQ ID NO: 13), AAGguacag,AAGguacgg, AAGguacug, AAGguagacc (SEQ ID NO: 14), AAGguagag, AAGguagcg,AAGguagua, AAGguagug, AAGguauac, AAGguauau, AAGguauauu (SEQ ID NO: 15),AAGguauca, AAGguaucg, AAGguaucu, AAGguauga, AAGguaugg, AAGguaugu,AAGguauuu, AAGgucaag, AAGgucaau, AAGgucucu, AAGgucuggg (SEQ ID NO: 16),AAGgucugu, AAGgugaccuu (SEQ ID NO: 17), AAGgugagau (SEQ ID NO: 18),AAGgugaguc (SEQ ID NO: 19), AAGgugccu, AAGgugggcc (SEQ ID NO: 20),AAGgugggu, AAGguggua, AAGguguau, AAGgugucu, AAGgugugc, AAGgugugu,AAGguguua, AAGguuaag, AAGguuagc, AAGguuagug (SEQ ID NO: 21), AAGguuca,AAGguuuaa, AAGguuuau, AAGguuugg, AAGuuaagg, AAGuuaaua, AAGuuagga,AAUguaaau, AAUguaagc, AAUguaagg, AAUguaauu, AAUguaugu, AAUgugagu,AAUgugugu, ACAguaaau, ACAgugagg, ACAguuagu, ACAguuuga, ACCaugagu,ACCgugaguu (SEQ ID NO: 22), ACGauaagg, ACGcuaagc, ACGguagcu, ACGgugaac,ACGgugagug (SEQ ID NO: 23), ACUguaaau, ACUguaacu, ACUguauu, ACUgugagug(SEQ ID NO: 24), AGAguaaga, AGAguaagg, AGAguaagu, AGAguagau, AGAguaggu,AGAgugaau, AGAgugagc, AGAgugagu, AGAgugcgu, AGCguaagg, AGCguaagu,AGCguacgu, AGCguaggu, AGCgugagu, AGGguaauga (SEQ ID NO: 25), AGGguagac,AGGguauau, AGGgugaau, AGGgugagg, AGGgugauc, AGGgugcaa, AGGgugucu,AGUguaagc, AGUguaagu, AGUgugagu, AGUgugaguac (SEQ ID NO: 26), AUAgucagu,AUAgugaau, AUCgguaaaa (SEQ ID NO: 27), AUCguuaga, AUGguaaaa, AUGguaacc,AUGguacau, AUGguaugu, AUGguauuu, AUGgucauu, AUGgugacc, AUUuuaagc,CAAGguaccu (SEQ ID NO: 28), CAAguaaac, CAAguaacu, CAAguaagc, CAAguaagg,CAAguaagua (SEQ ID NO: 29), CAAguaau, CAAguaugu, CAAguauuu, CAAgugaaa,CAAgugagu, CACgugagc, CACguuggu, CAGauaacu, CAGaugagg, CAGauuggu,CAGcugugu, CAGgcuggu, CAGgtaaggc (SEQ ID NO: 73), CAGguaaaa, CAGguaaag,CAGguaaccuc (SEQ ID NO: 31), CAGguaagac (SEQ ID NO: 32), CAGguaagc,CAGguaagu, CAGguaau, CAGguaaugc (SEQ ID NO: 33), CAGguaaugu (SEQ ID NO:34), CAGguacaa, CAGguacag, CAGguacagu (SEQ ID NO: 35), CAGguaccg,CAGguacug, CAGguagag, CAGguagcaa (SEQ ID NO: 36), CAGguaggagg (SEQ IDNO: 37), CAGguaggc, CAGguagguga (SEQ ID NO: 38), CAGguagua, CAGguagug,CAGguauag, CAGguauau, CAGguaucc, CAGguauga, CAGguaugg, CAGguaugu,CAGguauug, CAGgucaau, CAGgucagug (SEQ ID NO: 39), CAGgucuga, CAGgucugga(SEQ ID NO: 40), CAGgucuggu (SEQ ID NO: 41), CAGgucuuu, CAGgugagc,CAGgugaggg (SEQ ID NO: 42), CAGgugagugg (SEQ ID NO: 43), CAGgugaua,CAGgugcac, CAGgugcag, CAGgugcgc, CAGgugcug, CAGguggau, CAGgugggug (SEQID NO: 44), CAGgugua, CAGguguag, CAGguguau, CAGguguga, CAGgugugu,CAGguuaag, CAGguugau, CAGguugcu, CAGguuggc, CAGguuguc, CAGguuguu,CAGguuuagu (SEQ ID NO: 45), CAGguuugc, CAGguuugg, CAGuuuggu, CAUggaagac(SEQ ID NO: 46), CAUguaau, CAUguaauu, CAUguaggg, CAUguauuu, CCAguaaac,CCAgugaga, CCGguaacu, CCGgugaau, CCGgugacu, CCGgugagg, CCUauaagu,CCUaugagu, CCUguaaau, CCUguaagc, CCUguaauu, CCUgugaau, CCUgugauu,CGAguccgu, CGCauaagu, CGGguaau, CGGguauau, CGGguaugg, CGGgucauaauc (SEQID NO: 47), CGGgugggu, CGGguguau, CGGgugugu, CGUgugaau, CGUgugggu,CUGguauga, CUGgugaau, CUGgugaguc (SEQ ID NO: 48), CUGgugaguuc (SEQ IDNO: 49), CUGgugcau, CUGgugcuu, CUGguguga, CUGguuugu, CUGuuaag,CUGuugaga, GAAggaagu, GAAguaaac, GAAguaaau, GAAgucugg, GAAguggg,GAAgugugu, GAAuaaguu, GACaugagg, GAGaucugg, GAGaugagg, GAGCAGguaagcu(SEQ ID NO: 50), GAGcugcag, GAGgcaggu, GAGgcgugg, GAGgcuccc, GAGgtgggttt(SEQ ID NO: 74), GAGguaaag, GAGguaaga, GAGguaagag (SEQ ID NO: 52),GAGguaagcg (SEQ ID NO: 53), GAGguaauac (SEQ ID NO: 54), GAGguaauau (SEQID NO: 55), GAGguaaugu (SEQ ID NO: 56), GAGguacaa, GAGguagga, GAGguauau,GAGguauga, GAGguaugg, GAGgucuggu (SEQ ID NO: 57), GAGgugaag, GAGgugagg,GAGgugca, GAGgugccu, GAGgugcggg (SEQ ID NO: 58), GAGgugcug, GAGguguac,GAGguguau, GAGgugugc, GAGgugugu, GAGuuaagu, GAUaugagu, GAUguaaau,GAUguaagu, GAUguaauu, GAUguaua, GAUgugacu, GAUgugagg, GAUgugauu,GCAguaaau, GCAguagga, GCAguuagu, GCGaugagu, GCGgagagu, GCGguaaaa,GCGguaauca (SEQ ID NO: 59), GCGgugacu, GCGgugagca (SEQ ID NO: 60),GCGgugagcu (SEQ ID NO: 61), GCGguggga, GCGguuagu, GCUguaaau, GCUguaacu,GCUguaauu, GGAguaagg, GGAguaagu, GGAguaggu, GGAgugagu, GGAguuagu,GGCguaagu, GGCgucagu, GGGauaagu, GGGaugagu, GGGgtaagtg (SEQ ID NO: 75),GGGguaaau, GGGguaacu, GGGguacau, GGGgugacg, GGGgugagug (SEQ ID NO: 63),GGGgugcau, GGGguuggga (SEQ ID NO: 64), GGUguaagu, GUUCUCAgugug (SEQ IDNO: 66), UCAgugug, GUAgugagu, GUGguaagu, GUGguaagug (SEQ ID NO: 65),GUGgugagc, GUGgugagu, GUGgugauc, GUGguugua, GUUauaagu, GUUguaaau,GUUuugguga (SEQ ID NO: 67), UAGCAGguaagca (SEQ ID NO: 68), TGGgtacctg(SEQ ID NO: 76), UAGaugcgu, UAGguaaag, UAGguaccc, UAGguaggu, UAGguauau,UAGguauc, UAGguauga, UAGguauug, UAGgucaga, UAGgugcau, UAGguguau,UCAguaaac, UCAguaaau, UCAguaagu, UCAgugauu, UCCgugaau, UCCgugacu,UCCgugagc, UCUguaaau, UGAgugaau, UGGauaagg, UGGguaaag, UGGguacca,UGGguaugc, UGGguggau, UGGguggggg (SEQ ID NO: 70), UGGgugggug (SEQ ID NO:71), UGGgugugg, UGGguuagu, UGUgcaagu, UGUguaaau, UGUguacau, UUAguaaau,UUCauaagu, UUGguaaag, UUGguaaca, UUGguacau, UUGguagau, UUGgugaau,UUGgugagc, UUUauaagc or UUUgugagc.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2B. In some embodiments, an SMSMmodulates splicing of a splice site sequence comprising a sequenceAAAauaagu, AAGaugagc, AAGauuugu, AAGgaugag, AAGgcaaaa, AAGuuaagg,AAGuuaaua, AAGuuagga, ACCaugagu, ACGauaagg, ACGcuaagc, AGGguauau,AGGgugagg, AGGgugauc, AGGgugucu, AUGgugacc, AUUuuaagc, CAAgugagu,CACgugagc, CACguuggu, CAGauaacu, CAGaugagg, CAGaugagu, CAGauuggu,CAGcugugu, CAGgcgagu, CAGgcuggu, CAGgugacu, CAGguugau, CAGguugcu,CAGguuggc, CAGguuguu, CAGuuuggu, CAUguaggg, CAUguauuu, CCGgugaau,CCUauaagu, CCUaugagu, CCUgugaau, CGCauaagu, CGGguguau, CUGuuaag,CUGuugaga, GAAggaagu, GAAguaaau, GAAgucugg, GAAguggg, GAAgugugu,GAAuaaguu, GACaugagg, GAGaucugg, GAGaugagg, GAGgcaggu, GAGgcgugg,GAGgcuccc, GAGguaaga, GAGguagga, GAGgugagg, GAGuuaagu, GAUaugagu,GAUaugagu, GCAguagga, GCGaugagu, GCGgagagu, GCGgugacu, GCGguuagu,GCUguaacu, GGGaugagu, GUAgugagu, GUGgugagc, GUGgugauc, UAGaugcgu,UGGauaagg, UGGguacca, UGGguggau, UGGgugggug (SEQ ID NO: 71), UGUgcaagu,UUCauaagu, UUGguaaca, UUUauaagc or UUUgugagc.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2C or Table 2D. In someembodiments, an SMSM modulates splicing of a splice site sequencecomprising a sequence NGAguaag.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2C. In some embodiments, an SMSMmodulates splicing of a splice site sequence comprising a sequenceAGAguaag.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2D. In some embodiments, an SMSMmodulates splicing of a splice site sequence comprising a sequenceGGAguaag.

TABLE 2A Exemplary targets Splice Site Gene Disease Sequence DescriptionExon ABCA4 Stargardt disease, Macular GAGguaaag Non-mutated 5′ bulge 3Degeneration, Age-Related CGGguaugg Non-mutated 5′ bulge 4 AGUguaagcNon-mutated 5′ bulge 13 CCAguaaac IVS20+5G>A 20 CAGgugcac IVS28+5G>A 28AUGguacau IVS40+5G>A 40 AGAguaggu Non-mutated 5′ bulge 6 AAGguacugNon-mutated 5′ bulge 11 GGAguaggu Non-mutated 5′ bulge 20 ABCD1X-linked adrenoleukodystrophy (X- GAAguggg IVS1-1G>A 1 ALD) ACADMMedium-chain acyl-coA DH AAGguaaau IVS7+6G>U 8 deficiencyMutated 5′ bulge ACADSB 2-methylbutyryl-CoA dehydrogenase GGGgugcauIVS3+3A>G 3 deficiency ADA Adenosine deaminase deficiency CCAgugagaIVS5+6U>A 5 ADAMTS13 Thrombotic thrombocytopenic AGGguagac IVS13+5G>A 13purpura AGL Glycogen Storage Disease Type III GGCguaaguNon-mutated 5′ bulge 1 CUGguauga IVS6+3A>G 6 AAGguagugNon-mutated 5′ bulge 28 AGAguaagu Non-mutated 5′ bulge 31 AGTTreatment Resistant Hypertension AAGguaagcc (SEQ Non-mutated 5′ ss 1ID NO: 9) ALB Analbuminemia AACaugagga (SEQ c.1652+1G>A 12 ID NO: 4)ALDH3A2 Cancer, non-small cell lung cancer, CAGgucuggu (SEQNon-mutated 5′ bulge 2 Sjögren-Larrson syndrome ID NO: 41) AAGguuuauIVS5+5G>A 5 ALG6 ALG6-congenital disorder of UGUguaaau IVS3+5G>A 3glycosylation, ALG6-CDG ANGPTL3 Lipid disorders, Rare AAAguaagua (SEQNon-mutated 5′ ss 1 hyperlipidemias, Nonalcoholic fatty ID NO: 1)liver disease (NAFLD), Metabolic complications, Homozygous familialhypercholesterolemia (HoFH), Familial chylomicronemia syndrome (FCS) APCColorectal cancer, Familial CAAguaugu IVS9+3A>G 9 adenomatous polyposisCAAguauuu IVS9+5G>U 9 CAGguauau IVS14+3A>G 14 APOA1 UGGguaccug (SEQNon-mutated 5′ ss 1 ID NO: 69) APOB Familial hypercholesterolemia,AGAguaagu Non-mutated 5′ bulge 13 hypercholesterolemia HomozygousAAGgcaaaa IVS24+2 U>C 24 hypobetalipoproteinemia, familialhypercholesterolemia APOC3 Familial Chylomicronemia CAGguaaugc (SEQNon-mutated 5′ ss 1 Syndrome (FCS) and familial partial ID NO: 33)lipodystrophy (FPL) AR Androgen Sensitivity, prostate cancer CUGuuaagIVS4+1G>U 4 UUAguaaau IVS6+5G>A 6 ATM Ataxia-Telangiectasia, cancerAAGguagua Non-mutated 5′ bulge 2 UAGguauau IVS7+5dG>A 7 CAGguacagNon-mutated 5′ bulge 8 UUGguaaag Non-mutated 5′ bulge 9 AAGguuuaaIVS9+3A>U 9 AUCguuaga IVS21+3A>U 21 AUCgguaaaa (SEQ IVS21+5A 21ID NO: 27) AAGgucucu Non-mutated 5′ bulge 35 GAGguaaugu (SEQNon-mutated 5′ bulge 38 ID NO: 56) CAGauaacu IVS45+1G>A 45 GAGguaaagNon-mutated 5′ bulge 61 ATP7A Occipital Horn Syndrome, MenkesAAGguaaugu (SEQ Non-mutated 5′ bulge 3 Disease ID NO: 12)Occipital Horn Syndrome GUUguaaau IVS6+5G>A 6 Menkes Disease GUUauaaguIVS6+1G>A 6 Occipital Horn Syndrome, Menkes AAGguaaagNon-mutated 5′ bulge 10 Disease Occipital horn syndrome AAGguuaagIVS10+3A>U 10 Mutated 5′ bulge Menkes Disease CAGgucuuuIVS11+3A>C (mouse 11 model), consistent with patientOccipital Horn Syndrome, Menkes CAAguaaac IVS17+5G>A 17 DiseaseCUGguuugu IVS21+3A>U 21 ATP7B Wilson's disease AAAgugaguu (SEQNon-mutated 5′ ss 1 ID NO: 3) ATR Seckel syndrome 1 CAGguauugNon-mutated 5′ bulge 19 CAGgucuga Non-mutated 5′ bulge 28 ATXN2Spinocerebellar ataxia type 2 CAGgugggug (SEQ Non-mutated 5′ ss 1(SCA2), ALS ID NO: 44) GAGguggguuu Non-mutated 5′ ss 5 (SEQ ID NO: 51)ATXN3 Spinocerebellar ataxia type 3 (SCA3) AAAgugagug (SEQNon-mutated 5′ ss 1 ID NO: 2) B2M Cancer, colorectal cancer AGCgugaguNon-mutated 5′ bulge 1 BCL2-like 11 Autoimmune disease, tumorAGGguaauga (SEQ Non-mutated 5′ ss 3, 4 (BIM)development, Chronic Myeloid ID NO: 25) Leukemia drug resistanceGUUuugguga (SEQ ID NO: 67) BMP2K Cancer CAAguaaggMutation inducing loss of 14 U1snRNA affinity BRCA1 Breast CanerUGGguaaag Non-mutated 5′ bulge 1 AAGguguau IVS5+3A>G 5 AGGguauauIVS5-2A>G 5 AAGgugugc IVS13+6U>C 13 UUUgugagc IVS16+6U>C 16 UCUguaaauIVS18+5G>A 18 ACAguaaau IVS22+5G>A 22 BRCA2 Breast Cancer CAGgugugaIVS5+3A>G 5 UAGguauug Non-mutated 5′ bulge 14 CAGguaugaNon-mutated 5′ bulge 19 BTK Isolated growth hormone deficiency AAGgugguaNon-mutated 5′ bulge 2 type III, X-linked GAAguaaac IVS6+5G>A 6agammaglobulinemia (XLA), GAUgugagg IVS14+6U>G 14Cancer, Autoimmune disorders C3 Hereditary C3 deficiency UGGauaaggIVS18+1G>A 18 CACNA1B Pain, tactile neuropathic allodyniaGUGguaagug (SEQ Non-mutated 5′ ss 37a ID NO: 65) AAGguagacc (SEQNon-mutated 5′ ss 37b ID NO: 14) CACNA1C Type 1 Timothy's syndromeGAGCAGguaagcu G406R (G>A) 8a (SEQ ID NO: 50) Type 2 Timothy's syndromeUAGCAGguaagca G406R (G>A) 8 (SEQ ID NO: 68) GUUCUCAgugug G402R (G>A) 8(SEQ ID NO: 66) CALCA CGRP-related migraines CAUggaagac (SEQNon-mutated 5′ ss 4 ID NO: 46) CAT Acatalasemia and Pityriasis UUGguagauIVS4+5G>A 4 Versicolor, Autoimmune disease, cancer CD33Alzheimer's disease, acute myeloid CAGgugagugg Non-mutated 5′ ss 1leukemia (SEQ ID NO: 43) CD46 Autoimmune disorders, cancer,CAGguuuagu (SEQ Non-mutated 5′ ss 7 atypical hemolytic uremic syndromeID NO: 45) (aHUS), multiple sclerosis, CAGguuuagu (SEQ Non-mutated 5′ ss8 rheumatoid arthritis, age-related ID NO: 45)macular degeneration, asthma AAGguaucu Non-mutated 5′ ss 13 CDH1Cancer, hereditary diffuse gastric CAGguggau IVS14+5G>A 14cancer syndrome CDH23 Usher Syndrome and Nonsyndromic ACGgugaacIVS51+5G>A 51 Deafness AGCguaagg Non-mutated 5′ bulge 54 CFBHemolytic Uremic Syndrome, GAGguaagcg (SEQ Non-mutated 5′ ss 1(Complement Atypical 4 and Complement Factor B ID NO: 53) factor B)Deficiency CFTR Cystic Fibrosis CAUguaau −1G>U 8 Mutated 5′ bulgeAAAguaug −G>A 19 Mutated 5′ bulge AAGuuaaua IVS4+1G>U 4 ACAguuaguIVS6b+3d 6b CAGguaaugu (SEQ Non-mutated 5′ bulge 8 ID NO: 34) AAAguauguc.1766-1G>A 12 AAUguaugu c.1766-1G>U 12 AAGguauuu IVS12+5G>U 12AAGgugugu c.1766+3A>G 12 AAGgucugu c.1766+3A>C 12 AAGguaugaNon-mutated 5′ bulge 19 CACgugagc IVS20-1G>C 20 CHM ChoroideremiaUAGgucaga IVS13+3A>C 13 CLCN1 Myotonia congenita CAGguuaag IVS1+3A>U 1Mutated 5′ bulge COL11A1 Stickler syndrome, Cancer, MarshallGAGguaauac (SEQ Non-mutated 5′ bulge 7 syndrome ID NO: 54) AGCguaaguNon-mutated 5′ bulge 8 AGAguaagu Non-mutated 5′ bulge 29 AAGguaucaNon-mutated 5′ bulge 34 GGCguaagu Non-mutated 5′ bulge 50 GGCgucaguIVS50+3A>C 50 GGAguaagu Non-mutated 5′ bulge 64 COL11A2Otospondylomegaepiphyseal CCUgugaau IVS53+5G>A 53Dysplasia, Stickler syndrome COL1A1 Severe type III osteogenesisGGAguaagu Non-mutated 5′ bulge 5 imperfecta UCAguaaac IVS8+5G>A 8CCUaugagu IVS8+1G>A 8 AGAgugagu Non-mutated 5′ bulge 11 GCUguaaauIVS14+5G>A 14 AGCgugagu Non-mutated 5′ bulge 19 AGAguaaguNon-mutated 5′ bulge 30 COL1A2 Osteogenesis imperfecta AGAguagauIVS21+5G>A 21 Mutated 5′ bulge GAUguaaau IVS9+5G>A 9 AGAguagguNon-mutated 5′ bulge 21 AGAguaagu Non-mutated 5′ bulge 23 CGGguggguIVS26+3A>G 26 AGAguaagu Non-mutated 5′ bulge 30 CGUgugaau IVS33+5G>A 33CGUgugggu IVS33+4A>G 33 GCUguaaau IVS40+5G>A 40 COL2A1Chondrodysplasias, familial GUGguugua Non-mutated 5′ bulge 2osteoarthritis GGAguaagu Non-mutated 5′ bulge 7 AGAguaaguNon-mutated 5′ bulge 13 CCUgugauu IVS20+5G>U 20 UCUguaaau IVS24+5G>A 24AGAguaagu Non-mutated 5′ bulge 49 COL3A1 Ehlers-Danlos syndromeCCUguaagc IVS7+6U>C 7 UCAguaaau IVS8+5G>A 8 AGAguaaguNon-mutated 5′ bulge 10 GCAguuagu IVS14+3G>U 14Ehlers-Danlos syndrome IV CCUauaagu IVS16+1G>A 16 CGCauaagu IVS20+1G>A20 Ehlers-Danlos syndrome GAUgugauu IVS25+5G>U 25 ACUguaaau IVS27+5G>A27 ACUguauu IVS27+5G>U 27 AAGguagua Non-mutated 5′ bulge 29 GCUguaauuIVS37+5G>U 37 CCUguaaau IVS38+5G>A 38 CCUguaauu IVS38+5G>U 38 GAUgugacuIVS42+5G>C 42 Ehlers-Danlos syndrome IV GAUaugagu IVS42+1G>A 42Ehlers-Danlos syndrome CCUguaaau IVS45+5G>A 45 AGAguaaguNon-mutated 5′ bulge 46 COL4A5 Alport syndrome AGAguaaguNon-mutated 5′ bulge 4 AGAguaagu Non-mutated 5′ bulge 15 AAGgucuggg (SEQNon-mutated 5′ bulge 28 ID NO: 16) CAGgugcug Non-mutated 5′ bulge 39CAGguaaag Non-mutated 5′ bulge 52 COL6A1 Mild Bethlem myopathy GGGaugaguIVS3+1G>A 3 Autosomal-recessive isolated AAGguaugg Non-mutated 5′ bulge4 dystonia, dystonia CAGguaugg Non-mutated 5′ bulge 6 AAGguacggNon-mutated 5′ bulge 14 AAAguacau IVS29+5G>A 29 AGUguaaguNon-mutated 5′ bulge 38 COL7A1 Recessive dystrophic epidermolysisAGGgugauc IVS3-2A>G 3 bullosa Dominant dystrophic epidermolysisCAGguauag Non-mutated 5′ bulge 23 bullosa CAGguuugg Non-mutated 5′ bulge24 CAGguuugg Non-mutated 5′ bulge 27 AGGgugagg Non-mutated 5′ ss 73Recessive dystrophic epidermolysis GUAgugagu IVS95-1G>A 95 bullosaCOL9A2 Multiple epiphyseal dysplasia CCGgugagg IVS3+6U>G 3 CCGgugacuIVS3+5G>C 3 COLQ Congenital acetylcholinesterase UGGguggggg (SEQIVS16+3A>G 16 deficiency ID NO: 70) CREBBP Rubinstein-Taybi syndromeAAGguuca +3A>U 18 Mutated 5′ bulge CSTB Epilepsy:progressive myoclonusAAAguaga −1G>A 2 Mutated 5′ bulge CUL4BX-linked intellectual disability, CAGguaaaa Non-mutated 5′ bulge 14cancer CYBB X-linked chronic granulomatous GGGguaaau IVS2+5G>A 2 diseaseGCGguaaaa IVS3+5G>A 3 AAGguuagc IVS5+3A>U 5 UGAgugaau IVS6+5G>A 6 CYP17Congenital adrenal hyperplasia and UCAgugauu IVS2+5G>U 217-hydroxylase deficiency CUGgugaau IVS7+5G>A 7 CYP19Placental aromatase deficiency UGUgcaagu IVS6+2U>C 6 CYP27A1Cerebrotendineous xanthomatosis AACgugauu IVS7+5G>U 7 GAGguaggaIVS6-2C>A 6 GCAguagga IVS6-1G>A 6 DES Desmin-related myopathy GAGguguacIVS3+3A>G 3 DGAT2 Nonalcoholic steatohepatitis (NASH) GGGgugagug (SEQNon-mutated 5′ ss 1 ID NO: 63) DMD Duchenne's muscular dystrophy,GAUguaagu Non-mutated 5′ bulge 5 Duchenne and Becker muscular CAGguaaagNon-mutated 5′ bulge 8 dystrophy CAGgugugu Non-mutated 5′ bulge 14AUGgucauu IVS19+3A>C 19 AGAguaaga Non-mutated 5′ bulge 24 AAGggaaaaIVS26+2U>G 26 CAGguauau c.4250U>A 31 CAGguauau Non-mutated 5′ bulge 31AAGguaugag (SEQ Non-mutated 5′ ss 51 ID NO: 7) CAAguaacu IVS62+5G>C 62GCUguaacu IVS64+5G>C 64 GCUguaacu IVS64+5G>C 64 GAUguaauu IVS66+5G>U 66CCGguaacu IVS69+5G>C 69 AACgugacu IVS70+5G>C 70 DUX4 FSHDGGGguuggga (SEQ Non-mutated 5′ ss 1 ID NO: 64) DYSFLimb Girdle Muscular Dystrophy AGAgugcgu Non-mutated 5′ bulge 132B, Miyoshi myopathy, Miyoshi UGUguacau IVS45+5G>A 45Muscular Dystrophy 1 EGFR Cancer AACguaagu Non-mutated 5′ ss 4 ACAguuugaNon-mutated 5′ bulge 9 GUGgugagu Non-mutated 5′ bulge 22 EMDEmery-Dreifuss muscular dystrophy UAGguaccc IVS1+5G>C 1 ETV4Ovarian Cancer GAGcugcag Non-mutated 5′ bulge 5 F13A1 Cancer UUGgugagcIVS3+6C>U 3 UUGgugaau IVS3+5G>A 3 F5 Factor V deficiency AAGguaacuNon-mutated 5′ bulge 1 CAUguauuu IVS10-1G>U 10 AAGguuuggNon-mutated 5′ bulge 13 UGGguuagu IVS19+3A>U 19 AAGgucaagNon-mutated 5′ bulge 23 AAGguagag Non-mutated 5′ bulge 24 F7Factor VII deficiency UGGguggau IVS7+5G>A 7 UGGgugggug (SEQ IVS7+7A>G 7ID NO: 71) UGGguacca IVS7del[+3:+6] 7 F8 Hemophilia A AGGgugaauIVS3+5G>A 3 CAGgugugu IVS6+3A>G 6 CAGguguga IVS14+3A>G 14 AUAgugaauIVS19+5G>A 19 AUGguauuu IVS22+5G>U 22 AUAgucagu IVS23+3A>C 23 F11Factor XI, clotting disorders CAGguacagu(SEQ Non-mutated 5′ ss 1ID NO: 35) FAH Tyrosinemia type I, Chronic AAGguauguNon-mutated 5′ bulge 11 Tyrosinemia Type 1 CCGgugaau IVS12+5G>A 12 FANCAFanconi Anemia AGAguaaga Non-mutated 5′ bulge 4 AAGguagcgNon-mutated 5′ bulge 6 CUGgugcau IVS7+5G>A 7 CUGgugcuu IVS7+5G>U 7GAGgugcug Non-mutated 5′ bulge 10 CGAguccgu IVS16+3A>C 16 FANCCFanconi anemia AAUgugugu IVS4+4A>U 4 FANCGFanconi Anemia, Complementation CAGgugaua IVS4+3A>G 4Group G and Fanconi Anemia, Complementation Group A FBN1 Marfan SyndromeUUGguacau IVS11+5G>A 11 GAGguaugg Non-mutated 5′ bulge 13AAGguaauaa (SEQ Non-mutated 5′ bulge 14 ID NO: 11) CAGgucaau IVS25+5G>A25 CAUguaauu IVS37+5G>U 37 UAGgugcau IVS46+5G>A 46 UAGaugcgu IVS46+1G>A46 AAGguaaag Non-mutated 5′ bulge 60 FECH Erythropoietic protoporphyriaUAGguauc −3A>U 10 Mutated 5′ bulge GAGguauga Non-mutated 5′ bulge 2CAGguaugg Non-mutated 5′ bulge 4 AAGgugucu IVS10+3A>G 10 AAGguaucuNon-mutated 5′ bulge 10 FGA Common congenital afibrinogenemia UGGguguggIVS1+3A>G 1 GAGuuaagu IVS4+1G>U 4 FGFR2Craniosynostosis syndromes, cancer AGAguaagu Non-mutated 5′ bulge 3CAGguguau IVS3c+3A>G 3c FGG Dysfibrinogenaemia GCAguaaau IVS1+5G>A 1CAAgugaaa IVS3+5G>A 3 FIX Haemophilia B deficiency CGGgucauaauc c.519A>G5 (coagulation factor IX deficiency) (SEQ ID NO: 47) FLNAX-linked cardiac valvular dysplasia AGAguaagu Non-mutated 5′ bulge 19FOXM1 Cancer AAGguaaugu (SEQ Non-mutated 5′ bulge 4 ID NO: 12) UCAguaaguNon-mutated 5′ bulge 9 FRAS1 Fraser syndrome AAGguacggNon-mutated 5′ bulge 3 GGAgugagu Non-mutated 5′ bulge 5 AAGguauuuNon-mutated 5′ bulge 8 AAGguaucg Non-mutated 5′ bulge 17 AGCguagguNon-mutated 5′ bulge 22 AGAguaagu Non-mutated 5′ bulge 24 CAGguacaaNon-mutated 5′ bulge 53 GALC NASH GGAguuagu Non-mutated 5′ bulge 5 GBAGaucher's disease GAGguaagag (SEQ Non-mutated 5′ ss 2 ID NO: 52) GCGRDiabetes GCGgugagca (SEQ Non-mutated 5′ ss 1 ID NO: 60) GH1Growth hormone deficiency UCCgugagc IVS3+6U>C 3 UCCgugaau IVS3+5G>A 3UCCgugacu IVS3+5G>C 3 GGGgugacg IVS4+5G>C 4 GGGgugacg IVS4+5G>A 4 GHRAcromegaly GGGguaagug (SEQ Non-mutated 5′ ss 1 ID NO: 62) GHVMutation in placenta UUUauaagc IVS2+1G>A 2 GLA Fabry's diseaseAAGgugagau (SEQ Non-mutated 5′ ss 4 ID NO: 18) HADHATrifunctional protein deficiency or AAGgugucu IVS3+3A>G 3 LCHADAGUguaagu Non-mutated 5′ bulge 18 HBA2 Alpha-thalassemia GAGgcucccIVS1 del [2:+6] 1 HBB Beta-thalassemia CAGguuguu IVS1+5G>U 1 CACguugguIVS1-1G>C 1 CAGguuggc IVS1+6U>C 1 CAGauuggu IVS1+1G>A 1 CAGuuugguIVS1+1G>U 1 CAGgcuggu IVS1+2U>C 1 CAGguugau IVS1+5G>A 1 CAGguugcuIVS1+5G>C 1 AGGgugucu IVS2del[+4:+5] 2 HEXA Tay-Sachs Syndrome ACAguaaauIVS4+5G>A 4 CUGguguga IVS8+3A>G 8 GACaugagg IVS9+1G>A 9 HEXBSandhoff disease UUGguaaca IVS8+5G>C 8 HLCS Holocarboxylase synthetaseAAGgucaau IVS10+5G>A 10 deficiency HMBS Acute intermittent porphyriaGCGguuagu IVS1+3G>U 1 GCGgugacu IVS1+5G>C 1 HMGCLHereditary HL deficiency ACGcuaagc IVS7+1G>C 7 HNF1A diabetes AGCguaaguNon-mutated 5′ bulge 2 HPRT1 Somatic mutations in kidney tubularGUGgugagc IVS1del[−2:+34] 1 epithelial cells GUGgugauc IVS1+5G>U 1Lesch-Nyhan syndrome GAAggaagu IVS5+2U>G 5 GAAgugugu IVS5+3:4AA>GU 5GAAguaaau IVS5+5G>A 5 GAAuaaguu IVS5del[G1] 5 ACUguaaau IVS7+5G>A 7Hypoxanthine ACUguaacu IVS7+5G>C 7 phosphoribosyltransferase deficiencyAAUguaagc IVS8+6U>C 8 Mutation inducing loss of U1snRNA affinityAAUguaagg IVS8+6U>G 8 AAUguaaau IVS8+5G>A 8 AAUguaauu IVS8+5G>U 8 HPRT2Primary hyperthyroidism GGGauaagu IVS1+1G>A 1 HSF4 Congenital cataractsCAGguagug IVS12+4A>G 12 HSPG2 Schwartz-Jampel syndrome type 1 AGAgugaguNon-mutated 5′ ss 30 AGAguaagu Non-mutated 5′ ss 40 CAGguacagNon-mutated 5′ ss 61 HTT Huntington's disease CAGguacugNon-mutated 5′ ss 25 AAGguaaau Non-mutated 5′ ss 32 AGAguaaguNon-mutated 5′ ss 51 CUGgugaguc (SEQ Non-mutated 5′ ss 52 ID NO: 48)ACCgugaguu (SEQ Non-mutated 5′ ss 1 ID NO: 22) IDH1 GliomasCAGguaaccuc (SEQ Non-mutated 5′ ss 1 ID NO: 31) ACUgugagug (SEQNon-mutated 5′ ss 1 ID NO: 24) IDS Mucopolysaccharidosis type IIAUGguaacc IVS7+5G>C 7 (Hunter syndrome) AUUuuaagc IVS7-1:+1GG>UU 7IKBKAP Familial Dysautonomia, CAAguaagc IVS20+6U>C 20 DysautonomiaMutation inducing loss of U1snRNA affinity CAGguaugu Non-mutated 5′ ss27 AGCguacgu Non-mutated 5′ ss 33 IL7RAEncodes IL7RA, Multiple sclerosis AAGgugaccuu (SEQ Non-mutated 5′ ss 6ID NO: 17) INSR Breast Cancer GGCguaagu Non-mutated 5′ bulge 7 AGUguaaguNon-mutated 5′ bulge 20 ITGB2 Leukocyte adhesion deficiency UUCauaaguIVS7+1G>A 7 ITGB3 Glanzmann thrombasthenia GAUaugagu IVS4+1G>A 4 ITGB4Epidermolysis bullosa with GAGgugccu Non-mutated 5′ bulge 4congenital pyloric atresia CAGguagua Non-mutated 5′ bulge 33 JAG1Alagille syndrome CGGgugugu IVS11+3A>G 11 AGAgugagu Non-mutated 5′ bulge18 KLKB1 Hereditary angioedema CAGguagcaa (SEQ Non-mutated 5′ ss 1ID NO: 36) KRAS Cancer CAGguaagu Splice switching on 4a isoforms KRT5Dowling-Meara epidermolysis AAGaugagc IVS1+1G>A 1 bullosa simplex L1CAMCancer AAUgugagu Non-mutated 5′ bulge 2 AGAguaaga Non-mutated 5′ bulge14 CAGgugagc Non-mutated 5′ bulge 27 CAGguaaggc (SEQ Non-mutated 5′ ss 1ID NO: 30) LAMA2 Muscular dystrophy: merosin GAGgugca +3A>G 1 deficientMutated 5′ bulge LAMA3 Cancer, Junctional epidermolysis CAGguaaagNon-mutated 5′ bulge 16 bullosa AAGguaaugu (SEQ Non-mutated 5′ bulge 26ID NO: 12) CAGguagug Non-mutated 5′ bulge 27 AGCguaaguNon-mutated 5′ bulge 31 CAGguaccg Non-mutated 5′ bulge 40AAGguaaugu (SEQ Non-mutated 5′ bulge 45 ID NO: 12) AGAgugaguNon-mutated 5′ bulge 50 GAGguacaa Non-mutated 5′ bulge 57 UGGguaugcNon-mutated 5′ bulge 64 LDLR Familial hypercholesterolemia GAGgcguggIVS12+2U>C 12 LGALS3 NASH GCGgugagcu (SEQ Non-mutated 5′ ss 1 ID NO: 61)LMNA Hutchinson-Gilford progeria CAAgugagu c.1968-1G>A 10syndrome (HGPS) LPA Hyperlipoproteinemia, Type Iii and CAGguaagac (SEQNon-mutated 5′ ss 1 Familial Hyperlipidemia ID NO: 32) LPLFamilial hypercholesterolemia ACGauaagg IVS2+1G>A 2 LRRK2Parkinson's disease GCGguaauca (SEQ Non-mutated 5′ ss 1 ID NO: 59)AAGguaacaug (SEQ Non-mutated 5′ ss 31 ID NO: 8) CAGguagguga (SEQNon-mutated 5′ ss 41 ID NO: 38) MADD Cancer, Glioblastoma AAGguacagNon-mutated 5′ bulge 3 AAGgugggu Non-mutated 5′ bulge 16 AGAguaaggNon-mutated 5′ bulge 21 MAPT Frontotemporal Dementia AGUguaaguIVS10+3G>A 10 Alzheimer's disease, Frontotemporal Mutated 5′ bulgedementia and parkinsonism linked to AGUgugagu Non-mutated 5′ bulge 10chromosome 17, Progressive AGUgugaguac (SEQ Non-mutated 5′ bulge 10supranuclear palsy (PSP), ID NO: 26) Corticobasal degeneration (CBD),AAGguuagug (SEQ Non-mutated 5′ ss 1 Argyrophilic grain disease, Pick'sID NO: 21) disease AAGgugggcc (SEQ Non-mutated 5′ ss 2 ID NO: 20)CAGgugaggg (SEQ Non-mutated 5′ ss 3 ID NO: 42) AAGguaagcg (SEQNon-mutated 5′ bulge 5 ID NO: 10) MET Cancer AAGguauauu (SEQNon-mutated 5′ ss 14 ID NO: 15) MLH1 Colorectal cancer: non-polyposisCGGguaau −2A>G 6 Mutated 5′ bulge CAAguaau −1G>A 18 Mutated 5′ bulgeHereditary nonpolyposis colorectal CAGgugcag IVS6+3A>G 6cancer; Colorectal cancer: non- Mutated 5′ bulge polyposisHereditary nonpolyposis colorectal CAGgugcag IVS18+3A>G 18 cancerCAGguauag Non-mutated 5′ bulge 4 CAGguacag Non-mutated 5′ bulge 6CAGguaaugu (SEQ Non-mutated 5′ bulge 10 ID NO: 34) CAGguacagNon-mutated 5′ bulge 18 MSH2 Lynch syndrome AAGguaacaNon-mutated 5′ bulge 7 CAGguuugc Non-mutated 5′ bulge 10 MST1RCancer, Breast cancer, Colon cancer CAGguaggc Non-mutated 11 MTHFRSevere deficiency of MTHFR CAGaugagg IVS4+1G>A 4 MUTMethylmalonic acidemia AAGguauac Non-mutated 5′ bulge 3 AAGguguuaISV8+3A>G 8 GAGguaauau (SEQ Non-mutated 5′ bulge 10 ID NO: 55) MVKMevalonic aciduria CAGguaucc Non-mutated 5′ bulge 4 NF1Neurofibromatosis, UAGguguau IVS11+3A>G 11 Neurofibromatosis type 1Mutated 5′ bulge GGGguaacu IVS3+5G>C 3 Neurofibromatosis, CGGguguauIVS7+5G>A 7 Neurofibromatosis type I, Neurofibromatosis type IINeurofibromatosis, UAGguauau Non-mutated 5′ bulge 15Neurofibromatosis type 1 CAGguaaag Non-mutated 5′ bulge 21 GAGguaagaIVS27b del[+1:+10] 27b AAAauaagu IVS28+1G>A 28 NeurofibromatosisUAGguaaag Non-mutated 5′ bulge 34 CAAGguaccu (SEQ c.6724-4C>U 36ID NO: 28) AAGgugccu IVS36+3A>G 36 NF2 Neurofibromatosis, GAGgugaggIVS12 del+-14:+2 12 Neurofibromatosis type II GAGaugagg IVS12+1G>A 12NR1H4 Nonalcoholic steatohepatitis (NASH) CAAguaagua (SEQNon-mutated 5′ ss 1 ID NO: 29) OAT OAT deficiency CAGguugucNon-mutated 5′ bulge 5 OPA1 Autosomal dominant optic atrophy CGGguauauIVS8+5G>A 8 OTC Ornithine transcarbamylase GAGgugugc IVS7+3A>G 7deficiency OXT Pain, endometritis, Chorioamnionitis AAGgugaguc (SEQNon-mutated 5′ ss 1 ID NO: 19) PAH Phenylketonuria CAGguguga IVS5+3A>G 5AGAguaagu Non-mutated 5′ bulge 6 CAGguguga IVS10+3A>G 10 GAGgugcggg (SEQNon-mutated 5′ ss 1 ID NO: 58) PBGD Acute intermittent porphyriaGCGaugagu IVS1+1G>A 1 GCGgagagu IVS1+2U>A 1 GCGgugacu IVS1+5G>C 1GCGguuagu IVS1+3G>U 1 CAUguaggg IVS10-1G>U 10 PCCA Propionic acidemiaGGUguaagu Non-mutated 5′ bulge 14 AAGguaugg Non-mutated 5′ bulge 18 PDH1Pyruvate dehydrogenase deficiency AAGguacag Non-mutated 5′ bulge 11 PGK1Pyruvate dehydrogenase deficiency AAGuuagga IVS4+1G>U 4 PHEXX-linked hypophosphatemic rickets AGAgugagu Non-mutated 5′ bulge 4AGAgugagu Non-mutated 5′ bulge 14 PKD2 Polycystic kidney diseaseAGUguaagu Non-mutated 5′ bulge 13 PKLR Pyruvate kinase deficiencyCAGgucugga (SEQ Non-mutated 5′ bulge 7 ID NO: 40) GCGguggga IVS9+3A>G 9PKM1 Cancer Cancer metabolism CUGgugaguuc (SEQ Non-mutated 5′ ss 9ID NO: 49) PKM2 Cancer, Cancer metabolism CAGguaggagg (SEQNon-mutated 5′ ss 10 ID NO: 37) PLEKHM1Autosomal recessive osteopetrosis AGAgugagu Non-mutated 5′ bulge 4type 6 PLKR Lymphoblastic leukemia AGUgugagu Non-mutated 5′ bulge 25POMT2 Limb-girdle muscular dystrophy GGAguaagg Non-mutated 5′ bulge 3CAGguaaugu (SEQ Non-mutated 5′ bulge 10 ID NO: 34) AGAguaaguNon-mutated 5′ bulge 11 AGUgugagu Non-mutated 5′ bulge 14 PRDM1B-cell lymphoma CAGgugcgc Non-mutated 5′ bulge 6 PRKAR1A Carney complex.GAGgugaag IVS8+3A>G 8 PROC Protein C deficiency ACAgugagg IVS3+3A>G 3PSEN1 Alzheimer's disease CAGguacag Non-mutated 5′ bulge 3 PTCH1Basal cell carcinoma GAGgugugu Non-mutated 5′ bulge 1 PTENCowden syndrome GAGgcaggu IVS4+2U>C 4 AAGauuugu IVS7+1G>A 7 PYGMMyophosphorylase deficiency ACCaugagu IVS14+1G>A 14 (McArdle disease)RP6KA3 Coffin Lowry Syndrome GAGguguau IVS6+3A>G 6 RPGRRetinitis pigmentosa CAGgugua +3A>G 4 Mutated 5′ bulge AAGguuuggNon-mutated 5′ bulge 3 CAGguauag Non-mutated 5′ bulge 4 CAGguguagIVS4+3A>G 4 X-linked retinitis pigmentosa (RP3) CUGuugaga IVS5+1G>U 5Retinitis pigmentosa AGGgugcaa IVS10+3A>G 10 RSK2 Coffin Lowry SyndromeGAGguauau IVS6+3A>G 6 SBCAD SBCAD deficiency GGGguacau IVS3+3A>G 3 SCNAAlpha-synuclein, Parkinson's UAGguaggu Non-mutated 5′ ss 2disease, Dementia with Lewy bodies CAGguaagc Non-mutated 5'bulge 3 (DLB)GAGguagga Non-mutated 5'bulge 5 SCN5A Cardiomyopathies GGCguaaguNon-mutated 5′ bulge 4 CAGgugugu Non-mutated 5′ bulge 8 SERPINA1Emphysema AAGuuaagg IVS2+1G>U 2 SH2D1A Lymphoproliferative syndrome: X-GAUguaua −1G>U 2 linked Mutated 5′ bulge SLC12A3 Gitelman syndromeGGCguaagu Non-mutated 5′ bulge 22 SLC6A8 X-linked mental retardationGGAgugagu Non-mutated 5′ bulge 3 ACGguagcu IVS10+5G>C 10 SMN2Spinal muscular atrophy GGAguaagu IVS7+6C>U 7 Mutation inducing loss ofU1snRNA affinity SOD1 Familial ALS AAGgcaaggg (SEQ Non-mutated 5′ ss 1ID NO: 5) GUGguaagu Non-mutated 5′ ss 4 SPINK5 Netherton syndromeCAGguaau IVS2+5G>A 2 AAGguagua Non-mutated 5′ bulge 20 SPTA1Hereditary blood disorders, AAGguauau Non-mutated 5′ bulge 3Elliptocytosis-2, Pyropoikilocytosis, Spherocytosis type 3Hereditary blood disorders, CAGguagag Non-mutated 5′ bulge 27Elliptocytosis-2, Pyropoikilocytosis UAGguauga Non-mutated 5′ bulge 41TMPRSS6 Beta-thalassemia, Iron toxicity AAGgcaggga (SEQNon-mutated 5′ ss 1 ID NO: 6) TP53 Cancers GAGgucuggu (SEQNon-mutated 5′ bulge 5 ID NO: 57) Colorectal tumors AUGgugacc IVS5+5G>C5 Squamous cell carcinoma GAAgucugg IVS6-1G>A 6 GAGaucugg IVS6+1G>A 6TRAPPC2 Spondyloepiphyseal dysplasia tarda AAGguacgg +4U>C 5Mutated 5′ bulge AAGguaugg Non-mutated 5′ bulge 4 TSC1Tuberous sclerosis AUGguaaaa Non-mutated 5′ bulge 9 AAGguaaugua (SEQNon-mutated 5′ bulge 14 ID NO: 13) TSC2 AGAgugaau +5G>A 2Mutated 5′ bulge Familial tuberous sclerosis AAGgaugag IVS37+2 ins [A]37 TSHB Thyroid stimulating hormone. CGGguauau IVS2+5G>A 2 TTNDilated cardiomyopathy CAGgugagc Non-mutated 5′ ss 1 TTR amyloidosisACGgugagug (SEQ Non-mutated 5′ ss 1 ID NO: 23) UBE3A Dup15q, Angelman'sCAGgucagug (SEQ Non-mutated 5′ ss 1 ID NO: 39) UGT1A1Crigler-Najjar syndrome type 1 CAGcugugu IVS1+1G>C 1 USH2AUsher syndrome type IIa CAGguauug Non-mutated 5′ bulge 19CAGguaaugu (SEQ Non-mutated 5′ bulge 28 ID NO: 34) AAGguaaagNon-mutated 5′ bulge 31 GGAguaagu Non-mutated 5′ bulge 34 AGAgugagcNon-mutated 5′ bulge 39 AUGguaugu Non-mutated 5′ bulge 70

TABLE 2B Exemplary targets Mutated Authentic Authentic SpliceSplice Site Site Cryptic Splice Site Gene Disease Sequence Mutation Exonsequence (Location) HBB Beta- CACguuggu IVS1−1G>C 1 GUGgugagg (IVS1 −16)thalassemia CAGguuggc IVS1+6U>C 1 AUGguuaag (IVS2 +48) CAGauugguIVS1+1G>A 1 AAGgugaac (IVS1 −38) CAGuuuggu IVS1+1G>U 1AAGgugaag (Exon2−135) CAGgcuggu IVS1+2U>C 1 CAGguugau IVS1+5G>A 1CAGguugcu IVS1+5G>C 1 CAGguuguu IVS1+5G>U 1 AGGgugucu IVS2 del[+4:+5] 2GCGaugagu IVS1+1G>A 1 PBGD Acute CAUguaggg IVS10-1G>U 10CGGgugggg (Exon10 −9) intermittent GCGgagagu IVS1+2U>A 1 porphyriaGCGgugacu IVS1+5G>C 1 GCGguuagu IVS1+3G>U 1 HBA2 Alpha- GAGgcucccIVS1 del[+2:+6] 1 GGGguaagg (Exon1 −49) thalassemia AR Androgen CUGuuaagIVS4+1G>U 4 Sensitivity ATM Ataxia- CAGauaacu IVS45+1G>A 45AGAgugacu (IVS45 +72) telangiectasia BRCA1 Breast Cancer UUUgugagcIVS16+6U>C 16 UAUguaaga (Exon5 −22) AGGguauau IVS5-2A>G 5UAGguauug (IVS16 +70) CYP27A1 Cerebrotendinous GAGguagga IVS6-2C>A 6GUGgugggu (Exon6 −89) xanthomatosis GCAguagga IVS6-1G>A 6 FAH ChronicCCGgugaau IVS12+5G>A 12 GAGgugggu (IVS112 Tyrosinemia +106) Type 1 TP53Colorectal AUGgugacc IVS5+5G>C 5 tumors FGA Common GAGuuaagu IVS4+1G>U 4GGAguuaag (Exon4 −66) congenital UAAguauua (Exon4 −36) afibrinogenemiaPTEN Cowden AAGauuugu IVS7+1G>A 7 CAUguaagg (IVS7 +76) syndromeGAGgcaggu IVS4+2U>C 4 UGT1A1 Crigler-Najjar CAGcugugu IVS1+1G>C 1GAGgugacu (Exon1 −141) syndrome type 1 CFTR Cystic Fibrosis CACgugagcIVS20-1G>C 20 AUUgugagg (Exon4 −93) AAGuuaaua IVS4+1G>U 4 COL7A1Dominant AGGgugagg Exon73 del[−98:−71] 73 CUGguauuc (Exon73 −62)Dystrophic epidermolysis bullosa KRT5 Dowling-Meara AAGaugagc IVS1+1G>A1 AGGgugagg (Exon1 −66) epidermolysis bullosa simplex DMD Duchenne andGCUguaacu IVS64+5G>C 64 AAGggaaaa Becker (IVS26+2U>G) muscular dystrophyCOL3A1 Ehlers-Danlos GAUaugagu IVS42+1G>A 42 GGAguaagc (IVS16 +24)syndrome IV CCUauaagu IVS16+1G>A 16 CGCauaagu IVS20+1G>A 20 LPL FamilialACGauaagg IVS2+1G>A 2 CAGguggga (IVS2 +143) hypercholesterolemiaGAGguuggu (IVS2 +247) AGAgugagg (IVS2 +383) LDLR Familial GAGgcguggIVS12+2U>C 12 UACguacga (IVS12 +12) hypercholesterolemia TSC2 FamilialAAGgaugag IVS37+2ins[A] 37 CCGgugagg (Exon37 −29) tuberous sclerosis F7FVII deficiency UGGgugggug (SEQ IV57+7A>G 7 UGGgugggu (IVS7 +38)ID NO: 71) UGGguggau IVS7+5G>A 7 UGGguacca IVS7del[+3:+6] 7 ITGB3Glanzmann GAUaugagu IVS4+1G>A 4 CAGgugugg (IVS4 +28) thrombasthenia C3Hereditary C3 UGGauaagg IVS18+1G>A 18 GAAgugagu (Exon18 −61) deficiencyHMGCL Hereditary HL ACGcuaagc IVS7+1G>C 7 GGGguauuu (IVS7 +79)deficiency APOB Homozygous AAGgcaaaa IVS24+2U>C 24hypobetalipoproteinemia LMNA Hutchinson- CAAgugagu IVS11-1G>A 11CAGgugggc (Exon 11) Gilford progeria CAGgugacu IVS11+5G>C 11CAGgugggc (Exon 11) syndrome CAGaugagu IVS11+1G>A 11 CAGgugggc (Exon 11)(HGPS) CAGgcgagu IVS11+2U>C 11 CAGgugggc (Exon 11) HPRT1 Lesch-NyhanGAAggaagu IVS5+2U>G 5 AAGguaagc (IVS5 +68) syndrome GAAguguguIVS5+3:4AA>GU 5 GAAguaaau IV55+5G>A 5 GAAuaaguu IVS5del[G1] 5 ITGB2Leukocyte UUCauaagu IVS7+1G>A 7 AGGgugggg (IVS7 +65) adhesion deficiencyFBN1 Marfan UAGaugcgu IVS46+1G>A 46 GAAgucagu (IVS46 +34) syndrome GCKMaturity onset CCUgugagg (Exon4 −24) diabetes of the young (MODY) COL6A1Mild Bethlem GGGaugagu IVS3+1G>A 3 CAAguacuu (Exon3 −66) myopathy IDSMucopolysaccharidosis AUUuuaagc IVS7-1:+1GG>UU 7 CUGgugagu (IVS7 +23)type II (Hunter syndrome) GHV Mutation in UUUauaagc IVS2+1G>A 2UGGguaaug (IVS2 +13) placenta YGM Myophosphorylase ACCaugagu IVS14+1 G>A14 CAGgugaag (Exon14 −67) deficiency (McArdle disease) NF1Neurofibromatosis AAAauaagu IVS28+1G>A 28 AACguuaag (Exon27b −69) type IGAGguaaga IVS27b del[+1:+10] 27b AAGguauuc (Exon28 −4) NF2Neurofibromatosis GAGgugagg IVS12 del[−14:+2] 12 GAUguacgg (Exon7 −23)type II GAGaugagg IVS12+1G>A 12 AAGgugcug (Exon12−38) CGGguguauIVS7+5G>A 7 GAGgugcug (Exon12 −53) ACGguguga (Exon7 −28) PGK1Phosphoglycerate AAGuuagga IVS4+1G>U 4 GGGgugagg (IVS4 +31) kinasedeficiency CYP19 Placental UGUgcaagu IVS6+2U>C 6 aromatase deficiencyPKD1 Polycystic CAGguggcg (Exon43 −66) kidney disease 1 COL7A1 RecessiveGUAgugagu IVS95-1G>A 95 GGGgucagu (Exon95 −7) dystrophic AGGgugaucIVS3-2A>G 3 UCCgugagc (Exon 3 −104) epidermolysis bullosa Risk forAAGuuaagg IVS2+1G>U 2 AGGguacuc (Exon2 −84) emphysema Sandhoff UUGguaacaIVS8+5G>C 8 AAUguuggu (Exon8 −4) disease MTHFR Severe CAGaugaggIVS4+1G>A 4 deficiency of MTHFR F5 Severe factor V CAUguauuu IVS10−1G>U10 UCUguaaga (Exon10 −35) deficiency COL1Al Severe type III CCUaugaguIVS8+1G>A 8 UUGguaaga osteogenesis CCUgugaau IVS8+5G>A 8(IVS8 G +97; exon 8 ±26) imperfecta CUGgugagc (IVS8 +97)CUGgugaca (Exon34 −8) HPRT1 Somatic GUGgugagc IVS1del[−2:+34] 1CAGguggcg (IVS1 +50) mutations in GUGgugauc IVS1+5G>U 1 kidney tubularepithelial cells TP53 Squamous cell GAAgucugg IVS6−1G>A 6 carcinomaGAGaucugg IVS6+1G>A 6 HXA Tay-Sachs GACaugagg IVS9+1 G>A 9AGGgugggu (IVS9 +18) Syndrome ABCD1 X-linked GAAguggg IVS1−1G>A 1CAGguuggg (IVS1 +10) adrenoleukodystrophy (X-ALD) RPGR X-linkedCUGuugaga IVS5+1G>U 5 CAUguaauu (Exon5 −76) retinitis pigmentosa (RP3)

^(A) TABLE 2C Exemplary targets with AGAguaag splice site sequenceGenomic Genomic Gene Chr Location Location Strand EPHA3 3 8960444489604474 + PCOTH 13 23361677 23361707 + NDFIP2 13 79005577 79005607 +FZD6 8 104409805 104409835 + PTPN3 9 111222509 111222539 − AFP 474537190 74537220 + CBX3 7 26212640 26212670 + PHACTR4 1 2867537528675405 + TAF2 8 120826286 120826316 − KCNT2 1 194552885 194552915 −PRIM1 12 55431073 55431103 − CDH9 5 26941809 26941839 − SLC38A1 1244883044 44883074 − HDX X 83643077 83643107 − RAB23 6 57194060 57194090− STX3 11 59312981 59313011 + DNAH3 16 21053065 21053095 − SSX3 X48100997 48101027 − NSMAF 8 59670657 59670687 − XRN2 20 2128349521283525 + EVC2 4 5715719 5715749 − ERCC8 5 60223605 60223635 − QRSL1 6107210285 107210315 + CEP110 9 122943672 122943702 + FANCA 16 8840482288404852 − DYNC1H1 14 101544412 101544442 + TRIML1 4 189298099189298129 + MKL2 16 14213752 14213782 + CHAF1A 19 4369058 4369088 +CCDC11 18 46031110 46031140 − ALS2CL 3 46704576 46704606 − C13orf1 1349390214 49390244 − JAK1 1 65079706 65079736 − PAN2 12 54998272 54998302− PRKG1 10 52897587 52897617 + KREMEN1 22 27824926 27824956 + ADAMTS9 364611717 64611747 − PDS5B 13 32228079 32228109 + PTPRM 18 83746698374699 + DPP4 2 162570485 162570515 − L3MBTL2 22 39955591 39955621 +EFCAB3 17 57837751 57837781 + GRHPR 9 37412815 37412845 + ARHGEF18 197434826 7434856 + MLX 17 37977597 37977627 + ABCB5 7 20649508 20649538 +MAP4K4 2 101814730 101814760 + L1CAM X 152786433 152786463 − CLPB 1171683001 71683031 − GNB5 15 50203946 50203976 − TRAF3IP3 1 208021411208021441 + WDR26 1 222673827 222673857 − ARHGAP1 11 46675131 46675161 −PPP4C 16 30001341 30001371 + MRPS35 12 27768371 27768401 + WDR17 4177254715 177254745 + CLIC2 X 154162429 154162459 − ARS2 7 100323401100323431 + MYO3A 10 26483743 26483773 + EPS15 1 51701917 51701947 −ANK3 10 61570100 61570130 − CNOT1 16 57148251 57148281 − FBXO38 5147770506 147770536 + PLXNC1 12 93142207 93142237 + DMD X 3239260832392638 − TMEM27 X 15587044 15587074 − CDH10 5 24570962 24570992 −GOLT1B 12 21546134 21546164 + NUMA1 11 71412952 71412982 − IMMT 286226686 86226716 − SSX9 X 48050476 48050506 − SSX5 X 47941095 47941125− PPP1R12A 12 78790703 78790733 − TBCEL 11 120429636 120429666 + MYO9B19 17167267 17167297 + PRPF40B 12 48316028 48316058 + C10orf137 10127414448 127414478 + PDK4 7 95060931 95060961 − MEGF11 15 6399552463995554 − FLJ35848 17 40102396 40102426 + SLC13A1 7 122556119 122556149− MADD 11 47270708 47270738 + ADAM10 15 56723361 56723391 − MYH2 1710380556 10380586 − IL5RA 3 3121571 3121601 − RLN3 19 1400215314002183 + CCDC81 11 85803988 85804018 + SENP3 17 7408890 7408920 +ACSS2 20 32977730 32977760 + TRIM65 17 71399473 71399503 − LOC390110 1144028232 44028262 + SENP6 6 76388046 76388076 + PIK3C2G 12 1860768418607714 + SLC38A4 12 45458323 45458353 − HDAC5 17 39526192 39526222 −MGAM 7 141380633 141380663 + YARS 1 33020576 33020606 − C1R 12 71325607132590 − TIMM50 19 44670682 44670712 + SEC24A 5 134038791 134038821 +NOS2A 17 23138815 23138845 − FBXO18 10 6003311 6003341 + PKHD1L1 8110482978 110483008 + GSDMB 17 35315874 35315904 − C8orf33 8 146249321146249351 + PROCR 20 33222668 33222698 + FEZ2 2 36661921 36661951 −KIAA1033 12 104025754 104025784 + FANK1 10 127575199 127575229 + COMTD110 76664358 76664388 − REC8 14 23716414 23716444 + ATG4A X 107267755107267785 + GTPBP4 10 1045505 1045535 + PLCG1 20 39234328 39234358 +CDH24 14 22593539 22593569 − PRRG2 19 54783686 54783716 + KIF5A 1256256413 56256443 + C1orf130 1 24794575 24794605 + ARFGEF2 20 4703859147038621 + NME7 1 167534402 167534432 − SEL1L 14 81022370 81022400 − MME3 156369265 156369295 + PRIM2 6 57293302 57293332 + DNAJC13 3 133724516133724546 + PPP4R1L 20 56246657 56246687 − LUM 12 90026010 90026040 −ZNF37A 10 38424723 38424753 + SNRK 3 43348791 43348821 + SPAG9 1746511928 46511958 − JAK2 9 5063770 5063800 + C1orf114 1 167654859167654889 − CSE1L 20 47140951 47140981 + MRPS28 8 81077773 81077803 −NSMCE2 8 126183896 126183926 + NUBPL 14 31138321 31138351 + C5orf34 543544988 43545018 − MRPL39 21 25886979 25887009 − MTF2 1 9335374893353778 + FANCM 14 44720643 44720673 + EPB41L5 2 120601882 120601912 +ADAMTS20 12 42146706 42146736 − RFC4 3 187995125 187995155 − PIAS1 1566226077 66226107 + CUL5 11 107465545 107465575 + COL5A2 2 189615675189615705 − FN1 2 215951127 215951157 − PROSC 8 37749550 37749580 + LHX69 124015690 124015720 − SCYL3 1 168114383 168114413 − MALT1 18 5451878854518818 + C15orf42 15 87944905 87944935 + DIP2A 21 46773509 46773539 +WDR44 X 117454800 117454830 + KIN 10 7865034 7865064 − FGFR2 10123313990 123314020 − OSBPL8 12 75287532 75287562 − TCEB3 1 2395618723956217 + MYO19 17 31929016 31929046 − APOB 2 21104688 21104718 −RP13-36C9. X 134715052 134715082 + RP13-36C9. X 134777728 134777758 −CT45-6 X 134794978 134795008 − XX-FW88277 X 134680521 134680551 + CEP1109 122959964 122959994 + SPATS1 6 44428573 44428603 + C9orf114 9130631194 130631224 − STK17B 2 196712573 196712603 − CCDC18 1 9345599993456029 + NCOA1 2 24803064 24803094 + TTLL5 14 75199304 75199334 +SH3PXD2A 10 105474002 105474032 − DOCK4 7 111192394 111192424 − MTDH 898804424 98804454 + COL24A1 1 86145449 86145479 − ADAMTS6 5 6463155264631582 − SENP7 3 102529996 102530026 − PIGN 18 57928031 57928061 −TOP2B 3 25623650 25623680 − NUPL1 13 24787590 24787620 + OSBPL11 3126761897 126761927 − CCDC5 18 41954009 41954039 + COPS7B 2 232364112232364142 + POLN 4 2200608 2200638 − VTI1A 10 114418022 114418052 +SYTL5 X 37833769 37833799 + CETP 16 55561399 55561429 + LMLN J 199185727199185757 + C11orf70 11 101442577 101442607 + LMBRD2 5 36145788 36145818− DNTTIP2 1 94111247 94111277 − ECM2 9 94304600 94304630 − PRKG1 1053563656 53563686 + C16orf38 16 1477302 1477332 − RBM45 2 178696609178696639 + C1orf94 1 34416282 34416312 + GRIA1 5 152869544 152869574 +HDAC3 5 140988294 140988324 − IPO4 14 23727246 23727276 − MYOM2 82077714 2077744 + NARG1 4 140501217 140501247 + HEPACAM2 7 9265948792659517 − SDK2 17 68955333 68955363 − FBXO15 18 69958923 69958953 −SNX6 14 34120502 34120532 − BBOX1 11 27097953 27097983 + C3orf23 344417815 44417845 + ETS2 21 39108171 39108201 + CDC16 13 114040792114040822 + CFH 1 194908901 194908931 + ANTXR2 4 81171785 81171815 −PIK3CG 7 106300268 106300298 + EDEM3 1 182968578 182968608 − IL1R2 2102002691 102002721 + KPNA5 6 117133001 117133031 + LHCGR 2 4877924248779272 − NOL10 2 10720520 10720550 − CYP3A4 7 99205311 99205341 −TTC17 11 43369687 43369717 + FAR2 12 29366109 29366139 + COL3A1 2189563316 189563346 + ZBTB20 3 115826398 115826428 − COL19A1 6 7090758770907617 + NUP160 11 47797486 47797516 − SCO1 17 10539767 10539797 −VWA3B 2 98283096 98283126 + COL3A1 2 189580894 189580924 + CYP3A43 799283798 99283828 + DHRS7 14 59690414 59690444 − MIB1 18 1768716217687192 + NLRC5 16 55670690 55670720 + POLR3D 8 22160707 22160737 +ATP11C X 138696982 138697012 − ADAM15 1 153296186 153296216 + FAM65C 2048645297 48645327 − SCN3A 2 165733476 165733506 − CYP3A5 7 9910214499102174 − COL1A1 17 45624324 45624354 − FGR 1 27820641 27820671 − MIER219 276619 276649 − SIPA1L3 19 43283691 43283721 + CDH11 16 6358315663583186 − SYCP1 1 115203939 115203969 + ASH1L 1 153652143 153652173 −FAM13B1 5 137351846 137351876 − COL4A5 X 107693797 107693827 + PRPF4B 63966684 3966714 + PTPN11 12 111424428 111424458 + LAMB1 7 107367654107367684 − PIK3R1 5 67627057 67627087 + FLNA X 153243216 153243246 −SKIV2L2 5 54698445 54698475 + RNFT1 17 55394667 55394697 − PDCD4 10112644255 112644285 + AHCTF1 1 245137460 245137490 − DHFR 5 7996543679965466 − UTP15 5 72899893 72899923 + TMEM156 4 38666850 38666880 −TNKS 8 9604951 9604981 + NFIA 1 61570831 61570861 + NT5C3 7 3302179133021821 − TNKS2 10 93580736 93580766 + COL11A1 1 103227646 103227676 −PCNX 14 70583560 70583590 + MEMO1 2 31999355 31999385 − LMBRD1 670467362 70467392 − NEDD4 15 54030850 54030880 − PPP3CB 10 7490121674901246 − C1orf71 1 244864497 244864527 + CAB39 2 231383266 231383296 +POMT2 14 76848378 76848408 − TP53INP1 8 96013458 96013488 − CDC14A 1100706223 100706253 + KLF3 4 38367880 38367910 + NEK1 4 170760224170760254 − PPP4R2 3 73192886 73192916 + KLF12 13 73285274 73285304 −PHTF1 1 114042391 114042421 − COL2A1 12 46674028 46674058 − KIAA1622 1493792679 93792709 + TTN 2 179343016 179343046 − PSD3 8 18534387 18534417− LACE1 6 108905173 108905203 + SLC28A3 9 86104300 86104330 − COPA 1158533741 158533771 − PAPOLG 2 60849514 60849544 + CENPI X 100268896100268926 + ARFGEF1 8 68328224 68328254 − EXOC4 7 133273347 133273377 +TIAM2 6 155607594 155607624 + MDGA2 14 46384703 46384733 − BRCC3 X153972293 153972323 + MEGF10 5 126804443 126804473 + WDTC1 1 2748134827481378 + EMCN 4 101605587 101605617 − FUT9 6 96575555 96575585 + NPM15 170752572 170752602 + GPR160 3 171280364 171280394 + OSGEPL1 2190334602 190334632 − SGPL1 10 72274386 72274416 + CEP192 18 1302856313028593 + CHN1 2 175491492 175491522 − FLJ36070 19 53911758 53911788 −CELSR3 3 48652095 48652125 − GLT8D1 3 52704461 52704491 − COL14A1 8121423851 121423881 + SAAL1 11 18074878 18074908 − SH3TC2 5 148386600148386630 − SEC31A 4 84014772 84014802 − LVRN 5 115357435 115357465 +TLK2 17 57984833 57984863 + KIF5B 10 32349940 32349970 − EML5 1488282266 88282296 − TMF1 3 69176317 69176347 − TMF1 3 69155880 69155910− TRIM44 11 35641889 35641919 + PTK2 8 141925525 141925555 − MLL5 7104468691 104468721 + ABCB1 7 87034021 87034051 − SGOL2 2 201148414201148444 + PAWR 12 78512224 78512254 − NUBP1 16 10769375 10769405 +PHLDB2 3 113142167 113142197 + ISL2 15 74416322 74416352 + CNOT7 817145306 17145336 − UTX X 44823525 44823555 + COL5A2 2 189631804189631834 − DSCC1 8 120925014 120925044 − RB1CC1 8 53705567 53705597 −PLCB4 20 9401479 9401509 + ASPM 1 195328789 195328819 − ERMP1 9 58010955801125 − LIMK2 22 29986048 29986078 + HERC1 15 61733355 61733385 − CHD916 51854495 51854525 + THOC2 X 122599559 122599589 − SCN11A 3 3896189038961920 − SLC39A10 2 196281798 196281828 + PLCB1 20 8717354 8717384 +CXorf41 X 106348840 106348870 + CENTB2 3 196547261 196547291 − UNC5C 496382587 96382617 − DNAH8 6 39060046 39060076 + POMT2 14 7682484276824872 − MAGT1 X 76983383 76983413 − HSPA9 5 137921441 137921471 −PTPRK 6 128339479 128339509 − RP1 8 55697386 55697416 + PTPN4 2120434984 120435014 + C19orf42 19 16627033 16627063 − TG 8 133982965133982995 + PIGT 20 43481629 43481659 + CDC42BPB 14 102495705 102495735− TOM1L1 17 50382471 50382501 + USP39 2 85716749 85716779 + POSTN 1337058903 37058933 - PAH 12 101773028 101773058 - ARHGEF2 1 154191301154191331 - RBM39 20 33773060 33773090 - C21orf70 21 45204496 45204526 +GAS2L3 12 99540276 99540306 + UXT X 47401510 47401540 - C16orf48 1666257459 66257489 - CMIP 16 80282931 80282961 + CA11 19 5383460253834632 - PHKB 16 46251964 46251994 + ADAMTS9 3 64602548 64602578 −SETD3 14 99001777 99001807 − DENND2D 1 111532831 111532861 − GAB1 4144600066 144600096 + COL4A2 13 109888370 109888400 + PADI4 1 1755552617555556 + MYOM3 1 24260121 24260151 − ARPC3 12 109367624 109367654 −TBC1D3G 17 31873637 31873667 − USP6 17 4981754 4981784 + COG3 1344958696 44958726 + ATP6V1G3 1 196776306 196776336 − KIR2DL5B 19 237531237561 + KIR3DL2 19 60069161 60069191 + KIR3DL3 19 59938621 59938651 +HTT 4 3186721 3186751 + CEP192 18 13086291 13086321 + TEAD1 11 1285915912859189 + CD4 12 6775799 6775829 + SUCLG2 3 67662185 67662215 − VTI1B14 67192870 67192900 − L3MBTL 20 41598497 41598527 + GCG 2 162710280162710310 − MCF2L2 3 184428763 184428793 − MYCBP2 13 76590460 76590490 −AP2A2 11 971284 971314 + GRAMD3 5 125829912 125829942 + ATAD5 1726245279 26245309 + PDS5A 4 39540218 39540248 − GRM3 7 8630714286307172 + TG 8 134030355 134030385 + SPAG9 17 46430788 46430818 −PLEKHA7 11 16849206 16849236 − KATNAL2 18 42840008 42840038 + COL5A2 2189629928 189629958 − ERN2 16 23629322 23629352 − TFRC 3 197264670197264700 − TET2 4 106384369 106384399 + KRTCAP2 1 153411649 153411679 −MEGF10 5 126802143 126802173 + IWS1 2 127977417 127977447 − COL2A1 1246656548 46656578 − FAM20A 17 64062497 64062527 − PDIA3 15 4184268141842711 + CDC2L5 7 40084960 40084990 + SMARCA1 X 128473446 128473476 −NFRKB 11 129257540 129257570 − CPXM2 10 125629701 125629731 − BCS1L 2219235631 219235661 + NFIX 19 13045295 13045325 + SPECC1L 22 2305038023050410 + NAG 2 15350096 15350126 − KIF16B 20 16426242 16426272 − AKAP312 4621310 4621340 − PROX1 1 212228672 212228702 + MATN2 8 9910271699102746 + STAMBPL1 10 90663180 90663210 + EPHB1 3 136451008 136451038 +TTPAL 20 42548745 42548775 + PVRL2 19 50077446 50077476 + ZNF618 9115837321 115837351 + COL4A5 X 107710609 107710639 + FAM13C1 10 6079214960792179 − VPS35 16 45272068 45272098 − SPP2 2 234624463 234624493 +FAM19A1 3 68670706 68670736 + NRXN1 2 50576531 50576561 − HIPK3 1133326925 33326955 + CAPN9 1 228992543 228992573 + CEP170 1 241406611241406641 − FGFR1OP 6 167358357 167358387 + ADCY8 8 131917689 131917719− MAGI1 3 65403491 65403521 − UNC45B 17 30505858 30505888 + C16orf33 1646598 46628 + GRN 17 39783979 39784009 + KIF9 3 47293760 47293790 − LMO211 33847452 33847482 − C13orf15 13 40930591 40930621 + FNBP1L 1 9377119893771228 + CCDC102B 18 64657128 64657158 + C15orf29 15 32226677 32226707− ARHGAP18 6 129970715 129970745 trem C9orf98 9 134692499 134692529 −GRIA3 X 122389656 122389686 + DNAI1 9 34473463 34473493 + PIWIL3 2223475355 23475385 − SLC4A2 7 150394766 150394796 + CRKRS 17 3492985134929881 + OBFC2B 12 54905731 54905761 + C14orf118 14 7571277175712801 + DCTN3 9 34608657 34608687 − COL4A1 13 109656997 109657027 −CDCA8 1 37938765 37938795 + PARVB 22 42863716 42863746 + FGFR1OP2 1226982895 26982925 + STXBP1 9 129414525 129414555 + BMPR2 2 203129484203129514 + SNRP70 19 54293758 54293788 + ACADL 2 210793600 210793630 −TBC1D8B X 105950866 105950896 + MUC2 11 1073587 1073617 + POMT2 1476823313 76823343 − CAPSL 5 35946209 35946239 − BRSK2 11 14292101429240 + ERGIC3 20 33605556 33605586 + DDA1 19 17286183 17286213 + CDK813 25872672 25872702 + TP63 3 191068410 191068440 + INPP5D 2 233757891233757921 + MAPK8IP3 16 1714664 1714694 + TNFRSF8 1 12108681 12108711 +AMBRA1 11 46396023 46396053 − F3 1 94774093 94774123 − HSPG2 1 2205924122059271 − RHPN2 19 38209234 38209264 − RP11-265F1 1 15682467 15682497 +ELA2A 1 15662589 15662619 + GRM4 6 34115917 34115947 − GOLT1A 1202449617 202449647 − LGMN 14 92254829 92254859 − TNK2 3 197080749197080779 − LRP4 11 46867522 46867552 − SEC24A 5 134041726 134041756 +EFCAB4B 12 3658326 3658356 − MAPK9 5 179621274 179621304 − SH3RF2 5145415954 145415984 + NKAP X 118956705 118956735 − CALCOCO2 17 4427423344274263 + DDX1 2 15677956 15677986 + PRMT7 16 66912851 66912881 + TDRD313 59939499 59939529 + PPFIA2 12 80375659 80375689 − COL24A1 1 8602175186021781 − STAMBPL1 10 90671117 90671147 + KIF15 3 44865039 44865069 +ANXA11 10 81906098 81906128 − PIK3C2G 12 18415497 18415527 + COL29A1 3131625419 131625449 + ERMN 2 157892215 157892245 − GNAS 20 5690411956904149 + SULF2 20 45734333 45734363 − TRPM7 15 48654325 48654355 −ALAS1 3 52208481 52208511 + COPZ2 17 43466212 43466242 − OLIG2 2133320189 33320219 + FAM13A1 4 89889929 89889959 − RPN1 3 129823681129823711 − SRP72 4 57028652 57028682 + LPCAT2 16 54137215 54137245 +SGCE 7 94066929 94066959 − C1orf107 1 208070996 208071026 + UTP18 1746698625 46698655 + UVRAG 11 75405657 75405687 + PRC1 15 8931880389318833 − CUBN 10 17125816 17125846 − NEK5 13 51574054 51574084 − EPHB33 185781875 185781905 + ZNF114 19 53466882 53466912 + CAMK1D 10 1290654212906572 + NOTCH1 9 138517439 138517469 − ADAL 15 41415301 41415331 +SPATA13 13 23758516 23758546 + CAMKK1 17 3740720 3740750 − C9orf86 9138837917 138837947 + FRAS1 4 79513021 79513051 + CENTG2 2 236614209236614239 + PTPRD 9 8330327 8330357 − UHRF1BP1 6 34910601 34910631 +JAK1 1 65084904 65084934 − LYST 1 233985385 233985415 − CPSF2 1491697328 91697358 + PUS10 2 61041015 61041045 − COL1A2 7 9388250393882533 + DPP4 2 162587495 162587525 − SEC24D 4 119905389 119905419 −ADCY10 1 166139733 166139763 − CDH8 16 60627469 60627499 − ZC3HAV1 7138396306 138396336 − SKAP1 17 43620188 43620218 − FAM23B 10 1810515018105180 + RTEL1 20 61779965 61779995 + ZNF365 10 63806686 63806716 +SAE1 19 52348122 52348152 + STARD6 18 50109699 50109729 − TBK1 1263170151 63170181 + SETD4 21 36335959 36335989 − ZWINT 10 5779094757790977 − GRIN2B 12 13611210 13611240 − TNFRSF10A 8 23110574 23110604 −TNFRSF10B 8 22937630 22937660 − ROCK2 2 11251817 11251847 − ABCA9 1764568586 64568616 − GRIA4 11 105302860 105302890 + EXO1 1 240082321240082351 + PRAME 22 21231362 21231392 − C8B 1 57170055 57170085 −PAPOLG 2 60867690 60867720 + CDH8 16 60416401 60416431 − KIAA0586 1458025330 58025360 + GSTCD 4 106907867 106907897 + STAG1 3 137635072137635102 − CLINT1 5 157148933 157148963 − KCNN2 5 113836745 113836775 +GART 21 33800135 33800165 − DDX24 14 93596181 93596211 − AKAP10 1719785715 19785745 − LRPPRC 2 43980093 43980123 − DOCK11 X 117654388117654418 + LAMA2 6 129506903 129506933 + HNRNPH1 5 178975689 178975719− RAB11FIP2 10 119795296 119795326 − COL9A1 6 71036722 71036752 − LRRC421 54186227 54186257 + KRIT1 7 91693760 91693790 − PLEKHA5 12 1929935119299381 + MLANA 9 5882536 5882566 + CCDC15 11 124334355 124334385 +CACNA2D1 7 81437911 81437941 − SCN1A 2 166621151 166621181 − SENP6 676480002 76480032 + DNAJA4 15 76345675 76345705 + AP4E1 15 4906361949063649 + LAMB1 7 107413687 107413717 − TCP11L2 12 105254106105254136 + GOLGB1 3 122884438 122884468 − C20orf74 20 20513493 20513523− WDFY2 13 51228584 51228614 + MGC34774 7 77817519 77817549 + DNAJC7 1737394932 37394962 − RPAP3 12 46347014 46347044 − PTK2B 8 2734357427343604 + RNF32 7 156128527 156128557 + COL22A1 8 139862336 139862366 −VAPA 18 9940550 9940580 + MGAT4A 2 98641097 98641127 − RYR3 15 3192036131920391 + MYB 6 135552699 135552729 + SPATA4 4 177351087 177351117 −FZD3 8 28465172 28465202 + CR1 1 205847289 205847319 + C18orf8 1819360712 19360742 + CHIC2 4 54609863 54609893 − TRIML2 4 189255193189255223 − WRNIP1 6 2715579 2715609 + INTU 4 128814803 128814833 +WDR67 8 124231534 124231564 + C1orf149 1 37747450 37747480 − ELA1 1250021279 50021309 − C12orf51 12 111115232 111115262 − LIMCH1 4 4133572641335756 + ROCK1 18 16793783 16793813 − COL4A6 X 107440618 107440648 −AGL 1 100153615 100153645 + WWC3 X 10062621 10062651 + GPATCH1 1938295344 38295374 + IFI44L 1 78867257 78867287 + NLRC3 16 35381203538150 − DCC 18 48995950 48995980 + ARHGEF18 19 7433205 7433235 + MPI15 72972181 72972211 + PTPN22 1 114169271 114169301 − KIAA1622 1493744641 93744671 + DEPDC2 8 69158162 69158192 + NARG2 15 5852744558527475 − COL25A1 4 109972969 109972999 − ENPP3 6 132040758 132040788 +UTRN 6 144900531 144900561 + CUBN 10 17022021 17022051 − TIAL1 10121326097 121326127 − USP38 4 144346814 144346844 + SIPA1L2 1 230686145230686175 − NUPL1 13 24791473 24791503 + SUPT16H 14 20901216 20901246 −KIAA1219 20 36608472 36608502 + JAK2 9 5070365 5070395 + GALNT3 2166323487 166323517 − ZC3HC1 7 129477503 129477533 − COL1A2 7 9387838793878417 + CBX1 17 43509210 43509240 − SMC5 9 72102942 72102972 + ANXA104 169342392 169342422 + XRN1 3 143566826 143566856 − CREBBP 16 37348803734910 − NOS1 12 116186061 116186091 − SMARCA5 4 144667048 144667078 +VPS29 12 109421707 109421737 − PLD1 3 172935333 172935363 − PIGF 246694321 46694351 − C1orf27 1 184621823 184621853 + TCF12 15 5514329855143328 + COL24A1 1 85999651 85999681 − MRAP2 6 84829415 84829445 +FOLH1 11 49161261 49161291 − PSMAL 11 89035044 89035074 + SH3PXD2B 5171741629 171741659 − KIAA0256 15 47088689 47088719 − C4orf18 4159271372 159271402 − NR4A3 9 101635542 101635572 + FAM184A 6 119342986119343016 − PDE8B 5 76743287 76743317 + DDX4 5 55116914 55116944 + ERN117 59511851 59511881 − COL12A1 6 75868020 75868050 − COPB2 3 140573239140573269 − ICA1 7 8147904 8147934 − NUP98 11 3759832 3759862 − GJA1 6121798662 121798692 + LRRC19 9 26989596 26989626 − IPO8 12 3070940530709435 − CDK5RAP2 9 122255539 122255569 − UTY Y 13944813 13944843 −EIF3A 10 120806226 120806256 − ASNSD1 2 190238407 190238437 + ^(A) Homosapiens (human) genome assembly GRCh37 (hg19) from Genome ReferenceConsortium

^(A) TABLE 2D Exemplary SMSM Splice Site Targets with GGAguaag splicesite sequence Genomic Genomic Gene Chr location location Strand CD1B 1156565768 156565798 − ZFYVE1 14 72514372 72514402 − LENG1 19 5935229759352327 − PRUNE2 9 78424060 78424090 − HLA-DPB1 6 33161542 33161572 +GSTO2 10 106047417 106047447 + BRSK1 19 60506032 60506062 + GAPDH 126517578 6517608 + TTLL9 20 29950014 29950044 + CACHD1 1 6482056064820590 + DPP3 11 66019521 66019551 + LRWD1 7 101892597 101892627 +CYFIP2 5 156685209 156685239 + KIAA1787 17 7165139 7165169 − KCNN2 5113850384 113850414 + SLC25A14 X 129301993 129302023 + CEL 9 134934051134934081 + TRPM3 9 72443834 72443864 − DPY19L2P2 7 102707805 102707835− COL17A1 10 105787368 105787398 − TRPM5 11 2383317 2383347 − ITGB1 1033254789 33254819 − ACTG2 2 73982100 73982130 + TECTB 10 114049297114049327 + SYCP2 20 57890379 57890409 − KIAA1166 X 64056670 64056700 −RTF1 15 39549867 39549897 + MGAM 7 141368693 141368723 + PCBP4 351970789 51970819 − ERCC1 19 50609045 50609075 − CGN 1 149764875149764905 + CACNA1G 17 46040364 46040394 + NT5C 17 70638855 70638885 −MGAT5 2 134815785 134815815 + SDK1 7 3975567 3975597 + RMND5B 5177503319 177503349 + HLA-G 6 29905434 29905464 + HP1BP3 1 2097566120975691 − KIAA0564 13 41191711 41191741 − SLC6A6 3 14464313 14464343 +NFKBIL2 8 145638852 145638882 − PRODH 22 17298487 17298517 − CACNA1H 161202124 1202154 + INTS3 1 152003306 152003336 + POMT2 14 7684241776842447 − KLK12 19 56226928 56226958 − FAM134A 2 219754156 219754186 +MKKS 20 10360316 10360346 − HPGD 4 175650861 175650891 − FKBP3 1444659824 44659854 − TXNDC10 18 64501126 64501156 − NUP88 17 52307365230766 − SV2C 5 75622897 75622927 + ADAM32 8 39222827 39222857 + SEZ617 24307287 24307317 − NUDT5 10 12277759 12277789 − PDZRN3 3 7353597373536003 − TP53I3 2 24161089 24161119 − SCN8A 12 50366493 50366523 +NLRC3 16 3547579 3547609 − CDK6 7 92090270 92090300 − RFT1 3 5312892453128954 − GSTCD 4 106966391 106966421 + DAZ2 Y 23782988 23783018 + DAZ2Y 25408223 25408253 + FCGBP 19 45124790 45124820 − ZNF326 1 9024588290245912 + ITPR2 12 26483311 26483341 − CHL1 3 411540 411570 + NKAIN2 6124645972 124646002 + COL11A1 1 103121327 103121357 − CNGA3 2 9836632198366351 + SYT6 1 114437864 114437894 − ARHGAP26 5 142373859 142373889 +PTPRN2 7 157596266 157596296 − EPHA4 2 221999412 221999442 − RUFY1 5178936728 178936758 + ATP13A5 3 194534217 194534247 − PELI2 14 5582509055825120 + BTAF1 10 93681242 93681272 + SIVA1 14 104294127 104294157 +APOH 17 61655880 61655910 − TGS1 8 56848817 56848847 + CMYA5 5 7912263379122663 + NLRP7 19 60141208 60141238 − CYP24A1 20 52208016 52208046 −B4GALNT3 12 439957 439987 + UTP20 12 100203775 100203805 + NEK11 3132475093 132475123 + CARKD 13 110072699 110072729 + C15orf60 1571630529 71630559 + PIP5K1A 1 149478263 149478293 + NLRC5 16 5566201655662046 + SCN2A 2 165872678 165872708 + PITRM1 10 3192024 3192054 −RRM1 11 4105047 4105077 + PKIB 6 122996196 122996226 + C9orf43 9115225584 115225614 + ADAM22 7 87630416 87630446 + HCK 20 3012617030126200 + MRPL11 11 65961135 65961165 − COL2A1 12 46677640 46677670 −TBPL1 6 134343076 134343106 + TM4SF20 2 227943859 227943889 − KIAA052812 22567611 22567641 − C11orf65 11 107783017 107783047 − PTPRT 2040377761 40377791 − ITFG1 16 46044129 46044159 − MAP2K1 15 6446680464466834 + HSF2BP 21 43877565 43877595 − RFTN1 3 16394213 16394243 −ITPR2 12 26759936 26759966 − OBFC2A 2 192254973 192255003 + WDR16 179442360 9442390 + OPTN 10 13191006 13191036 + C14orf101 14 5612148856121518 + ADRBK2 22 24404867 24404897 + TOM1L2 17 17710899 17710929 −C6orf118 6 165614944 165614974 − PDLIM5 4 95794799 95794829 + USP1 162686910 62686940 + HLTF 3 150250693 150250723 − ERBB4 2 211960899211960929 − C4orf29 4 129161828 129161858 + UTP20 12 100293650100293680 + CRYZ 1 74952835 74952865 − DCBLD1 6 117960234 117960264 +KIF3B 20 30378333 30378363 + AKNA 9 116161679 116161709 − RALGDS 9134965460 134965490 − TM6SF1 15 81579422 81579452 + PMFBP1 16 7071429870714328 − TBC1D29 17 25911845 25911875 + FAM161A 2 61927382 61927412 −TBC1D26 17 15587032 15587062 + ZNF169 9 96088900 96088930 + KIAA1409 1493218778 93218808 + NFE2L2 2 177807182 177807212 − PRKCA 17 6221353962213569 + CLPTM1 19 50172542 50172572 + MCM6 2 136350283 136350313 −TMEM194A 12 55750708 55750738 − SCN4A 17 59403212 59403242 − TUSC3 815645477 15645507 + GBGT1 9 135028946 135028976 − CCDC146 7 7672180176721831 + GFM1 3 159853935 159853965 + MSMB 10 51225827 51225857 +STAT6 12 55778539 55778569 − FAM176B 1 36562065 36562095 − NEB 2152054715 152054745 − MTIF2 2 55349202 55349232 − CLEC16A 16 1097440410974434 + ADAMTS12 5 33685400 33685430 − LOC389634 12 8434117 8434147 −TGM7 15 41356336 41356366 − SLC6A13 12 217337 217367 − C11orf30 1175911968 75911998 + DCUN1D4 4 52469883 52469913 + TEK 9 2715961227159642 + RRP1B 21 43920630 43920660 + MGC16169 4 107450517 107450547 −TMEM77 1 111464661 111464691 − ADCY3 2 24915204 24915234 − RALBP1 189503272 9503302 + EPHB2 1 23111664 23111694 + PDXK 21 4399692343996953 + SLC22A17 14 22891679 22891709 − GPR158 10 25724933 25724963 +LYN 8 57022821 57022851 + SFRS12 5 65476106 65476136 + DHRS9 2 169632008169632038 + CLK1 2 201437053 201437083 − SLC6A11 3 10840062 10840092 +COL1A1 17 45631570 45631600 − DVL3 3 185367140 185367170 + ITIH1 352796653 52796683 + NLRP8 19 61179466 61179496 + SNCAIP 5 121808311121808341 + SH3BGRL2 6 80440220 80440250 + PDE10A 6 165768699 165768729− OPN4 10 88408409 88408439 + C1orf87 1 60227396 60227426 − EFNA4 1153306525 153306555 + KLHL20 1 172011589 172011619 + LAMA1 18 69484606948490 − BBS4 15 70804034 70804064 + SUPT6H 17 24025743 24025773 +MEGF10 5 126797085 126797115 + FGD6 12 94026394 94026424 − SMTN 2229825867 29825897 + PBRM1 3 52671173 52671203 − ATG16L2 11 7221280072212830 + KALRN 3 125859073 125859103 + DDEF1 8 131269521 131269551 −CSTF3 11 33077714 33077744 − ARHGAP8 22 43576693 43576723 + ZC3H7A 1611759772 11759802 − LARP7 4 113777829 113777859 + EFTUD2 17 4031813440318164 − UCK1 9 133391637 133391667 − CAPN3 15 40465431 40465461 +CNTN6 3 1389143 1389173 + PARD3 10 34730744 34730774 − TAF2 8 120866606120866636 − TSPAN7 X 38310537 38310567 + TP53BP2 1 222038424 222038454 −JMJD1C 10 64638813 64638843 − GRIA1 5 153058811 153058841 + RNGTT 689567986 89568016 − ABCC9 12 21957057 21957087 − SNX6 14 3416884834168878 − CGNL1 15 55531764 55531794 + ITGAL 16 30429943 30429973 +CYP4F3 19 15621076 15621106 + CYP4F2 19 15862106 15862136 − MS4A13 1160047987 60048017 + C2orf55 2 98820998 98821028 − AFP 4 7453403374534063 + COL15A1 9 100851846 100851876 + RIF1 2 152023655 152023685 +RPS6KA6 X 83246147 83246177 − DDX1 2 15670844 15670874 + MPDZ 9 1312997013130000 − PGM2 4 37526652 37526682 + RBL2 16 52058567 52058597 +CCDC131 12 70294865 70294895 − NDC80 18 2598814 2598844 + USH2A 1214238836 214238866 − VPS39 15 40243100 40243130 − DMTF1 7 8664857886648608 + RNF11 1 51508370 51508400 + DOCK10 2 225378003 225378033 −IQGAP2 5 75942749 75942779 + NLRP13 19 61108104 61108134 − ^(A) Homosapiens (human) genome assembly GRCh37 (hg19) from Genome ReferenceConsortium

Methods of Treatment

The compositions and methods described herein can be used for treating ahuman disease or disorder associated with aberrant splicing, such asaberrant pre-mRNA splicing. The compositions and methods describedherein can be used for treating a human disease or disorder bymodulating mRNA, such as pre-mRNA. In some embodiments, the compositionsand methods described herein can be used for treating a human disease ordisorder by modulating splicing of a nucleic acid even when that nucleicacid is not aberrantly spliced in the pathogenesis of the disease ordisorder being treated.

Provided herein are methods of treating cancer or a non-cancer diseaseor condition in a mammal in need thereof. The method can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof, to a mammal with acancer or a non-cancer disease or condition. In some embodiments, thepresent disclosure relates to the use of an SMSM as described herein forthe preparation of a medicament for the treatment, prevention and/ordelay of progression of cancer or a non-cancer disease or condition. Insome embodiments, the present disclosure relates to the use of a stericmodulator as described herein for the treatment, prevention and/or delayof progression of cancer or a non-cancer disease or condition.

In some embodiments, an effective amount in the context of theadministration of an SMSM compound or a pharmaceutically acceptable saltthereof, or composition or medicament thereof refers to an amount of anSMSM compound or a pharmaceutically acceptable salt thereof to a patientwhich has a therapeutic effect and/or beneficial effect. In certainspecific embodiments, an effective amount in the context of theadministration of an SMSM compound or a pharmaceutically acceptable saltthereof, or composition or medicament thereof to a patient results inone, two or more of the following effects: (i) reduces or amelioratesthe severity of a disease; (ii) delays onset of a disease; (iii)inhibits the progression of a disease; (iv) reduces hospitalization of asubject; (v) reduces hospitalization length for a subject; (vi)increases the survival of a subject; (vii) improves the quality of lifeof a subject; (viii) reduces the number of symptoms associated with adisease; (ix) reduces or ameliorates the severity of a symptomassociated with a disease; (x) reduces the duration of a symptomassociated with a disease associated; (xi) prevents the recurrence of asymptom associated with a disease; (xii) inhibits the development oronset of a symptom of a disease; and/or (xiii) inhibits of theprogression of a symptom associated with a disease. In some embodiments,an effective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to restore the amount of a RNAtranscript of a gene to the amount of the RNA transcript detectable inhealthy patients or cells from healthy patients. In other embodiments,an effective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to restore the amount an RNA isoformand/or protein isoform of gene to the amount of the RNA isoform and/orprotein isoform detectable in healthy patients or cells from healthypatients.

In some embodiments, an effective amount of an SMSM compound or apharmaceutically acceptable salt thereof is an amount effective todecrease the aberrant amount of an RNA transcript of a gene whichassociated with a disease. In some embodiments, an effective amount ofan SMSM compound or a pharmaceutically acceptable salt thereof is anamount effective to decrease the amount of the aberrant expression of anisoform of a gene. In some embodiments, an effective amount of an SMSMcompound or a pharmaceutically acceptable salt thereof is an amounteffective to result in a substantial change in the amount of an RNAtranscript (e.g., mRNA transcript), alternative splice variant orisoform.

In some embodiments, an effective amount of an SMSM compound or apharmaceutically acceptable salt thereof is an amount effective toincrease or decrease the amount of an RNA transcript (e.g., an mRNAtranscript) of gene which is beneficial for the prevention and/ortreatment of a disease. In some embodiments, an effective amount of anSMSM compound or a pharmaceutically acceptable salt thereof is an amounteffective to increase or decrease the amount of an alternative splicevariant of an RNA transcript of gene which is beneficial for theprevention and/or treatment of a disease. In some embodiments, aneffective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to increase or decrease the amountof an isoform of gene which is beneficial for the prevention and/ortreatment of a disease.

A method of treating cancer in a subject in need thereof can compriseadministering to the subject a therapeutically effective amount of acompound described herein or a pharmaceutically acceptable salt thereof.A method of treating a non-cancer disease or condition in a subject inneed thereof can comprise administering to the subject a therapeuticallyeffective amount of a compound described herein or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present disclosure relates to a method for thetreatment, prevention and/or delay of progression of cancer or anon-cancer disease or condition comprising administering an effectiveamount of a SMSM as described herein to a subject, in particular to amammal.

In some embodiments, an effective amount in the context of theadministration of an SMSM compound or a pharmaceutically acceptable saltthereof, or composition or medicament thereof refers to an amount of anSMSM compound or a pharmaceutically acceptable salt thereof to a patientwhich has a therapeutic effect and/or beneficial effect. In certainspecific embodiments, an effective amount in the context of theadministration of an SMSM compound or a pharmaceutically acceptable saltthereof, or composition or medicament thereof to a patient results inone, two or more of the following effects: (i) reduces or amelioratesthe severity of a disease; (ii) delays onset of a disease; (iii)inhibits the progression of a disease; (iv) reduces hospitalization of asubject; (v) reduces hospitalization length for a subject; (vi)increases the survival of a subject; (vii) improves the quality of lifeof a subject; (viii) reduces the number of symptoms associated with adisease; (ix) reduces or ameliorates the severity of a symptomassociated with a disease; (x) reduces the duration of a symptomassociated with a disease associated; (xi) prevents the recurrence of asymptom associated with a disease; (xii) inhibits the development oronset of a symptom of a disease; and/or (xiii) inhibits of theprogression of a symptom associated with a disease. In some embodiments,an effective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to restore the amount of a RNAtranscript of a gene to the amount of the RNA transcript detectable inhealthy patients or cells from healthy patients. In other embodiments,an effective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to restore the amount an RNA isoformand/or protein isoform of gene to the amount of the RNA isoform and/orprotein isoform detectable in healthy patients or cells from healthypatients.

In some embodiments, an effective amount of an SMSM compound or apharmaceutically acceptable salt thereof is an amount effective todecrease the aberrant amount of an RNA transcript of a gene whichassociated with a disease. In some embodiments, an effective amount ofan SMSM compound or a pharmaceutically acceptable salt thereof is anamount effective to decrease the amount of the aberrant expression of anisoform of a gene. In some embodiments, an effective amount of an SMSMcompound or a pharmaceutically acceptable salt thereof is an amounteffective to result in a substantial change in the amount of an RNAtranscript (e.g., mRNA transcript), alternative splice variant orisoform.

In some embodiments, an effective amount of an SMSM compound or apharmaceutically acceptable salt thereof is an amount effective toincrease or decrease the amount of an RNA transcript (e.g., an mRNAtranscript) of gene which is beneficial for the prevention and/ortreatment of a disease. In some embodiments, an effective amount of anSMSM compound or a pharmaceutically acceptable salt thereof is an amounteffective to increase or decrease the amount of an alternative splicevariant of an RNA transcript of gene which is beneficial for theprevention and/or treatment of a disease. In some embodiments, aneffective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to increase or decrease the amountof an isoform of gene which is beneficial for the prevention and/ortreatment of a disease. Non-limiting examples of effective amounts of anSMSM compound or a pharmaceutically acceptable salt thereof aredescribed herein. For example, the effective amount may be the amountrequired to prevent and/or treat a disease associated with the aberrantamount of an mRNA transcript of gene in a human subject. In general, theeffective amount will be in a range of from about 0.001 mg/kg/day toabout 500 mg/kg/day for a patient having a weight in a range of betweenabout 1 kg to about 200 kg. The typical adult subject is expected tohave a median weight in a range of between about 70 and about 100 kg.

In one embodiment, an SMSM described herein can be used in thepreparation of medicaments for the treatment of diseases or conditionsdescribed herein. In addition, a method for treating any of the diseasesor conditions described herein in a subject in need of such treatment,can involve administration of pharmaceutical compositions that includesat least one SMSM described herein or a pharmaceutically acceptablesalt, thereof, in a therapeutically effective amount to a subject.

In certain embodiments, an SMSM described herein can be administered forprophylactic and/or therapeutic treatments. In certain therapeuticapplications, the compositions are administered to a patient alreadysuffering from a disease or condition, in an amount sufficient to cureor at least partially arrest at least one of the symptoms of the diseaseor condition. Amounts effective for this use depend on the severity andcourse of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. Therapeutically effective amounts are optionallydetermined by methods including, but not limited to, a dose escalationclinical trial. In prophylactic applications, compositions containing anSMSM described herein can be administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Incertain embodiments, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). Doses employed for adult human treatmenttypically range of 0.01mg-5000 mg per day or from about 1 mg to about1000 mg per day. In some embodiments, a desired dose is convenientlypresented in a single dose or in divided doses.

For combination therapies described herein, dosages of theco-administered compounds can vary depending on the type of co-drug(s)employed, on the specific drug(s) employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially. If administration issimultaneous, the multiple therapeutic agents can be, by way of exampleonly, provided in a single, unified form, or in multiple forms.

Conditions and Diseases

The present disclosure relates to a pharmaceutical compositioncomprising a SMSM described herein for use in the treatment, preventionand/or delay of progression of a disease, disorder or condition. In someembodiments, the present disclosure relates to a pharmaceuticalcomposition comprising a SMSM described herein for use in the treatment,prevention and/or delay of progression of a disease, disorder orcondition in Table 2A, Table 2B, Table 2C and Table 2D.

A method of treating, preventing, or delaying a non-cancer disease orcondition disease can comprise administering a therapeutically effectiveamount of a compound described herein or a pharmaceutically acceptablesalt thereof to a subject with a disease, disorder or condition in Table2A, Table 2B, Table 2C and Table 2D.

In some embodiments, the present disclosure relates to a pharmaceuticalcomposition comprising a SMSM described herein for use in the treatment,prevention and/or delay of progression of cancer.

A method of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject with aliquid cancer. A method of treating, preventing, or delaying cancer cancomprise administering a therapeutically effective amount of a compounddescribed herein or a pharmaceutically acceptable salt thereof to asubject with a leukemia or lymphoma. A method of treating, preventing,or delaying cancer can comprise administering a therapeuticallyeffective amount of a compound described herein or a pharmaceuticallyacceptable salt thereof to a subject with a leukemia, acute myeloidleukemia, colon cancer, gastric cancer, macular degeneration, acutemonocytic leukemia, breast cancer, hepatocellular carcinoma, cone-roddystrophy, alveolar soft part sarcoma, myeloma, skin melanoma,prostatitis, pancreatitis, pancreatic cancer, retinitis, adenocarcinoma,adenoiditis, adenoid cystic carcinoma, cataract, retinal degeneration,gastrointestinal stromal tumor, Wegener's granulomatosis, sarcoma,myopathy, prostate adenocarcinoma, Hodgkin's lymphoma, ovarian cancer,non-Hodgkin's lymphoma, multiple myeloma, chronic myeloid leukemia,acute lymphoblastic leukemia, renal cell carcinoma, transitional cellcarcinoma, colorectal cancer, chronic lymphocytic leukemia, anaplasticlarge cell lymphoma, kidney cancer, breast cancer, cervical cancer.

A method of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject with asolid cancer or solid tumor.

In some embodiments, the tumor is selected from the group consisting ofadenocarcinoma, melanoma (e.g., metastatic melanoma), liver cancer(e.g., hepatocellular carcinoma, hepatoblastoma, liver carcinoma),prostate cancer (e.g., prostate adenocarcinoma, androgen-independentprostate cancer, androgen-dependent prostate cancer, prostatecarcinoma), sarcoma (e.g., leiomyosarcoma, rhabdomyosarcoma), braincancer (e.g., glioma, a malignant glioma, astrocytoma, brain stemglioma, ependymoma, oligodendroglioma, nonglial tumor, acousticneurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, primary brain lymphoma, anaplastic astrocytoma, juvenilepilocytic astrocytoma, a mixture of oligodendroglioma and astrocytomaelements), breast cancer (e.g., triple negative breast cancer,metastatic breast cancer, breast carcinoma, breast sarcoma,adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma,medullary breast cancer, mucinous breast cancer, tubular breast cancer,papillary breast cancer, inflammatory breast cancer), Paget's disease,juvenile Paget's disease, lung cancer (e.g., KRAS-mutated non-small celllung cancer, non-small cell lung cancer, squamous cell carcinoma(epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, small celllung cancer, lung carcinoma), pancreatic cancer (e.g., insulinoma,gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, carcinoidtumor, islet cell tumor, pancreas carcinoma), skin cancer (e.g., skinmelanoma, basal cell carcinoma, squamous cell carcinoma, melanoma,superficial spreading melanoma, nodular melanoma, lentigo malignantmelanoma, acrallentiginous melanoma, skin carcinoma), cervical cancer(e.g., squamous cell carcinoma, adenocarcinoma, cervical carcinoma),ovarian cancer (e.g., ovarian epithelial carcinoma, borderline tumor,germ cell tumor, stromal tumor, ovarian carcinoma), cancer of the mouth,cancer of the nervous system (e.g., cancer of the central nervoussystem, a CNS germ cell tumor), goblet cell metaplasia, kidney cancer(e.g., renal cell cancer, adenocarcinoma, hypernephroma, Wilms' tumor,fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer),renal cell carcinoma, renal carcinoma), bladder cancer (e.g.,transitional cell carcinoma, squamous cell cancer, carcinosarcoma),stomach cancer (e.g., fungating (polypoid), ulcerating, superficialspreading, diffusely spreading, liposarcoma, fibrosarcoma,carcinosarcoma), uterine cancer (e.g., endometrial cancer, endometrialcarcinoma, uterine sarcoma), cancer of the esophagus (e.g., squamouscancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoidcarcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma,verrucous carcinoma, and oat cell (small cell) carcinoma, esophagealcarcinomas), colon cancer (e.g., colon carcinoma), cancer of the rectum(e.g., rectal cancers), colorectal cancer (e.g., colorectal carcinoma,metastatic colorectal cancer, hereditary nonpolyposis colorectal cancer,KRAS mutated colorectal cancer), gallbladder cancer (e.g.,adenocarcinoma, cholangiocarcinoma, papillary cholangiocarcinoma,nodular cholangiocarcinoma, diffuse cholangiocarcinoma), testicularcancer (e.g., germinal tumor, seminoma, anaplastic testicular cancer,classic (typical) testicular cancer, spermatocytic testicular cancer,nonseminoma testicular cancer), embryonal carcinoma (e.g., teratomacarcinoma, choriocarcinoma (yolk-sac tumor)), gastric cancer (e.g.,gastrointestinal stromal tumor, cancer of other gastrointestinal tractorgans, gastric carcinomas), bone cancer (e.g., connective tissuesarcoma, bone sarcoma, cholesteatoma-induced bone osteosarcoma, Paget'sdisease of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma,malignant giant cell tumor, fibrosarcoma of bone, chordoma, periostealsarcoma, soft-tissue sarcoma, angiosarcoma (hemangiosarcoma),fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, alveolar soft partsarcoma), liposarcoma, lymphangiosarcoma, neurilemmoma,rhabdomyosarcoma, synovial sarcoma, cancer of the lymph node (e.g.,lymphangioendotheliosarcoma), adenoid cystic carcinoma, vaginal cancer(e.g., squamous cell carcinoma, adenocarcinoma, melanoma), vulvar cancer(e.g., squamous cell carcinoma, melanoma, adenocarcinoma, sarcoma,Paget's disease), cancer of other reproductive organs, thyroid cancer(e.g., papillary thyroid cancer, follicular thyroid cancer, medullarythyroid cancer, anaplastic thyroid cancer, thyroid carcinoma), salivarygland cancer (e.g., adenocarcinoma, mucoepidermoid carcinoma), eyecancer (e.g., ocular melanoma, iris melanoma, choroidal melanoma,cilliary body melanoma, retinoblastoma), penal cancers, oral cancer(e.g. squamous cell carcinoma, basal cancer), pharynx cancer (e.g.,squamous cell cancer, verrucous pharynx cancer), cancer of the head,cancer of the neck, cancer of the throat, cancer of the chest, cancer ofthe spleen, cancer of skeletal muscle, cancer of subcutaneous tissue,adrenal cancer, pheochromocytoma, adrenocortical carcinoma, pituitarycancer, Cushing's disease, prolactin-secreting tumor, acromegaly,diabetes insipidus, myxosarcoma, osteogenic sarcoma, endotheliosarcoma,mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma,cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma,sebaceous gland carcinoma, papillary carcinoma, papillaryadenocarcinomas, ependyoma, optic nerve glioma, primitiveneuroectodermal tumor, rhabdoid tumor, renal cancer, glioblastomamultiforme, neurofibroma, neurofibromatosis, pediatric cancer,neuroblastoma, malignant melanoma, carcinoma of the epidermis,polycythemia vera, Waldenstrom's macroglobulinemia, monoclonalgammopathy of undetermined significance, benign monoclonal gammopathy,heavy chain disease, pediatric solid tumor, Ewing's sarcoma, Wilmstumor, carcinoma of the epidermis, HIV-related Kaposi's sarcoma,rhabdomyosarcoma, thecomas, arrhenoblastomas, endometrial carcinoma,endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma,nasopharyngeal carcinoma, laryngeal carcinoma, hepatoblastoma, Kaposi'ssarcoma, hemangioma, cavernous hemangioma, hemangioblastoma,retinoblastoma, glioblastoma, Schwannoma, neuroblastoma,rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, urinary tractcarcinoma, abnormal vascular proliferation associated with phakomatoses,edema (such as that associated with brain tumors), Meigs' syndrome,pituitary adenoma, primitive neuroectodermal tumor, medullblastoma, andacoustic neuroma.

A method of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject withbasal cell carcinoma, goblet cell metaplasia, or a malignant glioma. Amethod of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject with acancer of the liver, breast, lung, prostate, cervix, uterus, colon,pancreas, kidney, stomach, bladder, ovary, or brain.

A method of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject with acancer of the head, neck, eye, mouth, throat, esophagus, esophagus,chest, bone, lung, kidney, colon, rectum or other gastrointestinal tractorgans, stomach, spleen, skeletal muscle, subcutaneous tissue, prostate,breast, ovaries, testicles or other reproductive organs, skin, thyroid,blood, lymph nodes, kidney, liver, pancreas, and brain or centralnervous system.

Specific examples of cancers that can be prevented and/or treated inaccordance with present disclosure include, but are not limited to, thefollowing: renal cancer, kidney cancer, glioblastoma multiforme,metastatic breast cancer; breast carcinoma; breast sarcoma;neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma;malignant melanoma; carcinomas of the epidermis; leukemias such as butnot limited to, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemias such as myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia leukemias and myclodysplasticsyndrome, chronic leukemias such as but not limited to, chronicmyelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairycell leukemia; polycythemia vera; lymphomas such as but not limited toHodgkin's disease, non-Hodgkin's disease; multiple myelomas such as butnot limited to smoldering multiple myeloma, nonsecretory myeloma,osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma andextramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonalgammopathy of undetermined significance; benign monoclonal gammopathy;heavy chain disease; bone cancer and connective tissue sarcomas such asbut not limited to bone sarcoma, myeloma bone disease, multiple myeloma,cholesteatoma-induced bone osteosarcoma, Paget's disease of bone,osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant celltumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangio sarcoma, neurilemmoma,rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but notlimited to, glioma, astrocytoma, brain stem glioma, ependymoma,oligodendroglioma, nonglial tumor, acoustic neurinoma,craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; breast cancer including butnot limited to adenocarcinoma, lobular (small cell) carcinoma,intraductal carcinoma, medullary breast cancer, mucinous breast cancer,tubular breast cancer, papillary breast cancer, Paget's disease(including juvenile Paget's disease) and inflammatory breast cancer;adrenal cancer such as but not limited to pheochromocytom andadrenocortical carcinoma; thyroid cancer such as but not limited topapillary or follicular thyroid cancer, medullary thyroid cancer andanaplastic thyroid cancer; pancreatic cancer such as but not limited to,insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secretingtumor, and carcinoid or islet cell tumor; pituitary cancers such as butlimited to Cushing's disease, prolactin-secreting tumor, acromegaly, anddiabetes insipius; eye cancers such as but not limited to ocularmelanoma such as iris melanoma, choroidal melanoma, and cilliary bodymelanoma, and retinoblastoma; vaginal cancers such as squamous cellcarcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamouscell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma,and Paget's disease; cervical cancers such as but not limited to,squamous cell carcinoma, and adenocarcinoma; uterine cancers such as butnot limited to endometrial carcinoma and uterine sarcoma; ovariancancers such as but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; cervicalcarcinoma; esophageal cancers such as but not limited to, squamouscancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoidcarcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma,verrucous carcinoma, and oat cell(small cell) carcinoma; stomach cancerssuch as but not limited to, adenocarcinoma, fungating (polypoid),ulcerating, superficial spreading, diffusely spreading, malignantlymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers;KRAS mutated colorectal cancer; colon carcinoma; rectal cancers; livercancers such as but not limited to hepatocellular carcinoma andhepatoblastoma, gallbladder cancers such as adenocarcinoma;cholangiocarcinomas such as but not limited to papillary, nodular, anddiffuse; lung cancers such as KRAS-mutated non-small cell lung cancer,non-small cell lung cancer, squamous cell carcinoma (epidermoidcarcinoma), adenocarcinoma, large-cell carcinoma and small-cell lungcancer; lung carcinoma; testicular cancers such as but not limited togerminal tumor, seminoma, anaplastic, classic (typical), spermatocytic,nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma(yolk-sac tumor), prostate cancers such as but not limited to,androgen-independent prostate cancer, androgen-dependent prostatecancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penalcancers; oral cancers such as but not limited to squamous cellcarcinoma; basal cancers; salivary gland cancers such as but not limitedto adenocarcinoma, mucoepidermoid carcinoma, and adenoidcysticcarcinoma; pharynx cancers such as but not limited to squamous cellcancer, and verrucous; skin cancers such as but not limited to, basalcell carcinoma, squamous cell carcinoma and melanoma, superficialspreading melanoma, nodular melanoma, lentigo malignant melanoma,acrallentiginous melanoma; kidney cancers such as but not limited torenal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma,transitional cell cancer (renal pelvis and/or uterer); renal carcinoma;Wilms' tumor; bladder cancers such as but not limited to transitionalcell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. Inaddition, cancers include myxosarcoma, osteogenic sarcoma,endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma,hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogeniccarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillarycarcinoma and papillary adenocarcinomas.

A method of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject with apediatric solid tumor, Ewing's sarcoma, Wilms tumor, neuroblastoma,neurofibroma, carcinoma of the epidermis, malignant melanoma, cervicalcarcinoma, colon carcinoma, lung carcinoma, renal carcinoma, breastcarcinoma, breast sarcoma, metastatic breast cancer, HIV-relatedKaposi's sarcoma, prostate cancer, androgen-independent prostate cancer,androgen-dependent prostate cancer, neurofibromatosis, lung cancer,non-small cell lung cancer, KRAS-mutated non-small cell lung cancer,malignant melanoma, melanoma, colon cancer, KRAS-mutated colorectalcancer, glioblastoma multiforme, renal cancer, kidney cancer, bladdercancer, ovarian cancer, hepatocellular carcinoma, thyroid carcinoma,rhabdomyosarcoma, acute myeloid leukemia, or multiple myeloma.

In some embodiments, cancers and conditions associated therewith thatare prevented and/or treated in accordance with the present disclosureare breast carcinomas, lung carcinomas, gastric carcinomas, esophagealcarcinomas, colorectal carcinomas, liver carcinomas, ovarian carcinomas,thecomas, arrhenoblastomas, cervical carcinomas, endometrial carcinoma,endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma,head and neck cancer, nasopharyngeal carcinoma, laryngeal carcinomas,hepatoblastoma, Kaposi's sarcoma, melanoma, skin carcinomas, hemangioma,cavernous hemangioma, hemangioblastoma, pancreas carcinomas,retinoblastoma, astrocytoma, glioblastoma, Schwannoma,oligodendroglioma, medulloblastoma, neuroblastomas, rhabdomyosarcoma,osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, thyroidcarcinomas, Wilm's tumor, renal cell carcinoma, prostate carcinoma,abnormal vascular proliferation associated with phakomatoses, edema(such as that associated with brain tumors), or Meigs' syndrome. Inspecific embodiment, the cancer an astrocytoma, an oligodendroglioma, amixture of oligodendroglioma and an astrocytoma elements, an ependymoma,a meningioma, a pituitary adenoma, a primitive neuroectodermal tumor, amedullblastoma, a primary central nervous system (CNS) lymphoma, or aCNS germ cell tumor.

In some embodiments, the cancer treated in accordance with the presentdisclosure is an acoustic neuroma, an anaplastic astrocytoma, aglioblastoma multiforme, or a meningioma. In some embodiments, thecancer treated in accordance with the present disclosure is a brain stemglioma, a craniopharyngioma, an ependyoma, a juvenile pilocyticastrocytoma, a medulloblastoma, an optic nerve glioma, primitiveneuroectodermal tumor, or a rhabdoid tumor.

A method of treating, preventing, or delaying a condition or disease cancomprise administering a therapeutically effective amount of a compounddescribed herein or a pharmaceutically acceptable salt thereof to asubject with acute myeloid leukemia, ALS, Alzheimer's disease,argyrophilic grain disease, cancer metabolism, chronic lymphocyticleukemia, colorectal carcinoma, corticobasal degeneration, cysticfibrosis, dilated cardiomyopathy, Duchenne muscular dystrophy,Ehlers-Danlos syndrome, endometrial cancer, Fabry's disease, familialdysautonomia, familial hypercholesterolemia, familial persistenthyperinsulinemic hypoglycemia, frontotemporal dementia, FTDP-17,gucher's disease, glioma, globular glial tauopathy, HIV-1, Huntington'sdisease, Hutchinson-Gilford progeria syndrome, hypercholesterolemia,Leber congenital amaurosis, migraine, multiple sclerosis,myelodysplastic syndromes, NASH, Niemann-Pick's, non-small cell lungcancer, pain, Parkinson's disease, phenylketonuria, Pick's disease,progressive supranuclear palsy, spinal muscular atrophy, spinocerebellarataxia type 2, or Wilson's disease.

A method of treating, preventing, or delaying a non-cancer disease orcondition disease can comprise administering a therapeutically effectiveamount of a compound described herein or a pharmaceutically acceptablesalt thereof to a subject with atypical hemolytic uremic syndrome(aHUS), cystic fibrosis, muscular dystrophy, polycysticautosomal-dominant kidney disease, cancer-induced cachexia, benignprostatic hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis,obesity, retinopathies (including diabetic retinopathy and retinopathyof prematurity), retrolental fibroplasia, neovascular glaucoma,age-related macular degeneration, exudative macular degeneration,thyroid hyperplasias (including Grave's disease), corneal and othertissue transplantation, epidemic keratoconjunctivitis, Vitamin Adeficiency, contact lens overwear, atopic keratitis, superior limbickeratitis, and pterygium keratitis sicca, viral infections, inflammationassociated with viral infections, chronic inflammation, lunginflammation, nephrotic syndrome, preeclampsia, ascites, pericardialeffusion (such as that associated with pericarditis), pleural effusion,Sjogren's syndrome, acne rosacea, phylectenulosis, syphilis, lipiddegeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpessimplex infection, Herpes zoster infections, protozoan infections,Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis,systemic lupus, polyarteritis, trauma, Wegener's sarcoidosis, Paget'sdisease, scleritis, Stevens-Johnson's disease, pemphigoid, radialkeratotomy, Eales' disease, Behcet's disease, sickle cell anemia,pseudoxanthoma elasticum, Stargardt's disease, pars planitis, chronicretinal detachment, vein occlusion, artery occlusion, carotidobstructive disease, chronic uveitis/vitritis, ocular histoplasmosis,Mycobacteria infections, Lyme's disease, Best's disease, myopia, opticpits, hyperviscosity syndromes, toxoplasmosis, sarcoidosis, trauma,post-laser complications, diseases associated with rubeosis(neovascularization of the iris and of the angle), and diseases causedby the abnormal proliferation of fibrovascular or fibrous tissue,including all forms of prolific vitreoretinopathy. Certain examples ofnon-neoplastic conditions that can be prevented and/or treated inaccordance with the methods described herein include viral infections,including but not limited to, those associated with viruses belonging toFlaviviridae, flavivirus, pestivirus, hepacivirus, West Nile virus,hepatitis C virus (HCV) or human papilloma virus (HPV), cone-roddystrophy, prostatitis, pancreatitis, retinitis, cataract, retinaldegeneration, Wegener's granulomatosis, myopathy, adenoiditis, germ celltumors, combined methylmalonic aciduria and homocystinuria, cblC type,Alzheimer's disease, hyperprolinemia, acne, tuberculosis, succinicsemialdehyde dehydrogenase deficiency, esophagitis, mental retardation,glycine encephalopathy, Crohn's disease, spina bifida, autosomalrecessive disease, schizophrenia, neural tube defects, myelodysplasticsyndromes, amyotropic lateral sclerosis, neuronitis, Parkinson'sdisease, talipes equinovarus, dystrophinopathies, cerebritis, bladderrelated disorders, cleft lip, cleft palate, cervicitis, spasticity,lipoma, scleroderma, Gitelman syndrome, poliomyelitis, paralysis,Aagenaes syndrome, oculomotor nerve paralysis, and spinal muscularatrophy.

A method of treating, preventing, or delaying a non-cancer disease orcondition disease can comprise administering a therapeutically effectiveamount of a compound described herein or a pharmaceutically acceptablesalt thereof to a subject with atypical hemolytic uremic syndrome(aHUS), Hutchinson-Gilford progeria syndrome (HGPS), Limb girdlemuscular dystrophy type 1B, Familial partial lipodystrophy type 2,Frontotemporal dementia with parkinsonism chromosome 17, Richardson'ssyndrome, PSP-Parkinsonism, Argyrophilic grain disease, Corticobasaldegeneration, Pick's disease, Globular glial tauopathy, GuadeloupeanParkinsonism, Myotonic dystrophy, Down Syndrome, NeonatalHypoxia-Ischemia, Familial Dysautonomia, Spinal muscular atrophy,Hypoxanthine phosphoribosyltransferase deficiency, Ehlers-Danlossyndrome, Occipital Horn Syndrome, Fanconi Anemia, Marfan Syndrome,thrombotic thrombocytopenic purpura, glycogen Storage Disease Type III,cystic fibrosis, neurofibromatosis, Tyrosinemia (type I), MenkesDisease, Analbuminemia, Congenital acetylcholinesterase deficiency,Haemophilia B deficiency (coagulation factor IX deficiency), Recessivedystrophic epidermolysis bullosa, Dominant dystrophic epidermolysisbullosa, Somatic mutations in kidney tubular epithelial cells,Neurofibromatosis type II, X-linked adrenoleukodystrophy (X-ALD), FVIIdeficiency, Homozygous hypobetalipoproteinemia, Ataxia-telangiectasia,Androgen Sensitivity, Common congenital afibrinogenemia, Risk foremphysema, Mucopolysaccharidosis type II (Hunter syndrome), Severe typeIII osteogenesis imperfecta, Ehlers-Danlos syndrome IV, Glanzmannthrombasthenia, Mild Bethlem myopathy, Dowling-Meara epidermolysisbullosa simplex, Severe deficiency of MTHFR, Acute intermittentporphyria, Tay-Sachs Syndrome, Myophosphorylase deficiency (McArdledisease), Chronic Tyrosinemia Type 1, Mutation in placenta, Leukocyteadhesion deficiency, Hereditary C3 deficiency, Neurofibromatosis type I,Placental aromatase deficiency, Cerebrotendinous xanthomatosis, Duchenneand Becker muscular dystrophy, Severe factor V deficiency,Alpha-thalassemia, Beta-thalassemia, Hereditary HL deficiency,Lesch-Nyhan syndrome, Familial hypercholesterolemia, Phosphoglyceratekinase deficiency, Cowden syndrome, X-linked retinitis pigmentosa (RP3),Crigler-Najjar syndrome type 1, Chronic tyrosinemia type I, Sandhoffdisease, Maturity onset diabetes of the young (MODY), Familial tuberoussclerosis, Polycystic kidney disease 1, or Primary Hyperthyroidism.

In some embodiments, non-cancer diseases that can be prevented and/ortreated in accordance with the disclosure of WO2016/19638₆ a1,WO2016/12834₃ a1, WO2015/02487₆ a2 and EP3053577A1. In some embodiments,non-cancer diseases that can be prevented and/or treated include, butare not limited to, atypical hemolytic uremic syndrome (aHUS),Hutchinson-Gilford progeria syndrome (HGPS), Limb girdle musculardystrophy type 1B, Familial partial lipodystrophy type 2, Frontotemporaldementia with parkinsonism chromosome 17, Richardson's syndrome,PSP-Parkinsonism, Argyrophilic grain disease, Corticobasal degeneration,Pick's disease, Globular glial tauopathy, Guadeloupean Parkinsonism,Myotonic dystrophy, Down Syndrome, Neonatal Hypoxia-Ischemia, FamilialDysautonomia, Spinal muscular atrophy, Hypoxanthinephosphoribosyltransferase deficiency, Ehlers-Danlos syndrome, OccipitalHorn Syndrome, Fanconi Anemia, Marfan Syndrome, thromboticthrombocytopenic purpura, glycogen Storage Disease Type III, cysticfibrosis, neurofibromatosis, Tyrosinemia (type I), Menkes Disease,Analbuminemia, Congenital acetylcholinesterase deficiency, Haemophilia Bdeficiency (coagulation factor IX deficiency), Recessive dystrophicepidermolysis bullosa, Dominant dystrophic epidermolysis bullosa,Somatic mutations in kidney tubular epithelial cells, Neurofibromatosistype II, X-linked adrenoleukodystrophy (X-ALD), FVII deficiency,Homozygous hypobetalipoproteinemia, Ataxia-telangiectasia, AndrogenSensitivity, Common congenital afibrinogenemia, Risk for emphysema,Mucopolysaccharidosis type II (Hunter syndrome), Severe type IIIosteogenesis imperfecta, Ehlers-Danlos syndrome IV, Glanzmannthrombasthenia, Mild Bethlem myopathy, Dowling-Meara epidermolysisbullosa simplex, Severe deficiency of MTHFR, Acute intermittentporphyria, Tay-Sachs Syndrome, Myophosphorylase deficiency (McArdledisease), Chronic Tyrosinemia Type 1, Mutation in placenta, Leukocyteadhesion deficiency, Hereditary C3 deficiency, Neurofibromatosis type I,Placental aromatase deficiency, Cerebrotendinous xanthomatosis, Duchenneand Becker muscular dystrophy, Severe factor V deficiency,Alpha-thalassemia, Beta-thalassemia, Hereditary HL deficiency,Lesch-Nyhan syndrome, Familial hypercholesterolemia, Phosphoglyceratekinase deficiency, Cowden syndrome, X-linked retinitis pigmentosa (RP3),Crigler-Najjar syndrome type 1, Chronic tyrosinemia type I, Sandhoffdisease, Maturity onset diabetes of the young (MODY), Familial tuberoussclerosis, or Polycystic kidney disease 1.

Methods of Administering

The compositions described herein can be administered to the subject ina variety of ways, including parenterally, intravenously, intradermally,intramuscularly, colonically, rectally or intraperitoneally. In someembodiments, the small molecule splicing modulator or a pharmaceuticallyacceptable salt thereof is administered by intraperitoneal injection,intramuscular injection, subcutaneous injection, or intravenousinjection of the subject. In some embodiments, the pharmaceuticalcompositions can be administered parenterally, intravenously,intramuscularly or orally. The oral agents comprising a small moleculesplicing modulator can be in any suitable form for oral administration,such as liquid, tablets, capsules, or the like. The oral formulationscan be further coated or treated to prevent or reduce dissolution instomach. The compositions of the present invention can be administeredto a subject using any suitable methods known in the art. Suitableformulations for use in the present invention and methods of deliveryare generally well known in the art. For example, the small moleculesplicing modulators described herein can be formulated as pharmaceuticalcompositions with a pharmaceutically acceptable diluent, carrier orexcipient. The compositions may contain pharmaceutically acceptableauxiliary substances as required to approximate physiological conditionsincluding pH adjusting and buffering agents, tonicity adjusting agents,wetting agents and the like, such as, for example, sodium acetate,sodium lactate, sodium chloride, potassium chloride, calcium chloride,sorbitan monolaurate, triethanolamine oleate, etc.

Pharmaceutical formulations described herein can be administrable to asubject in a variety of ways by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular, intramedullary injections, intrathecal,direct intraventricular, intraperitoneal, intralymphatic, intranasalinjections), intranasal, buccal, topical or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

In some embodiments, the pharmaceutical compositions described hereinare administered orally. In some embodiments, the pharmaceuticalcompositions described herein are administered topically. In suchembodiments, the pharmaceutical compositions described herein areformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, shampoos, scrubs,rubs, smears, medicated sticks, medicated bandages, balms, creams orointments. In some embodiments, the pharmaceutical compositionsdescribed herein are administered topically to the skin. In someembodiments, the pharmaceutical compositions described herein areadministered by inhalation. In some embodiments, the pharmaceuticalcompositions described herein are formulated for intranasaladministration. Such formulations include nasal sprays, nasal mists, andthe like. In some embodiments, the pharmaceutical compositions describedherein are formulated as eye drops. In some embodiments, thepharmaceutical compositions described herein are: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by inhalation to the mammal; and/or (e) administered bynasal administration to the mammal; or and/or (f) administered byinjection to the mammal; and/or (g) administered topically to themammal; and/or (h) administered by ophthalmic administration; and/or (i)administered rectally to the mammal; and/or (j) administerednon-systemically or locally to the mammal. In some embodiments, thepharmaceutical compositions described herein are administered orally tothe mammal. In certain embodiments, an SMSM described herein isadministered in a local rather than systemic manner. In someembodiments, an SMSM described herein is administered topically. In someembodiments, an SMSM described herein is administered systemically.

Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser thatcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

SMSMs suitable for injectable use include sterile aqueous solutions(where water soluble) or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersion. For intravenous administration, suitable carriers includephysiological saline, bacteriostatic water, Cremophor EL™ (BASF,Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, thecomposition must be sterile and should be fluid to the extent that easysyringability exists. It must be stable under the conditions ofmanufacture and storage and must be preserved against contamination frommicroorganisms such as bacteria and fungi. The carrier can be a solventor dispersion medium containing, for example, water, ethanol, polyol(for example, glycerol, propylene glycol, and liquid polyethyleneglycol, and the like), and suitable mixtures thereof The proper fluiditycan be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Prevention of the action ofmicroorganisms can be achieved by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, ascorbic acid,thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, polyalcohols such asmanitol, sorbitol, sodium chloride in the composition.

Dosing and Schedules

The SMSMs utilized in the methods of the invention can be, e.g.,administered at dosages that may be varied depending upon therequirements of the subject the severity of the condition being treatedand/or imaged, and/or the SMSM being employed. For example, dosages canbe empirically determined considering the type and stage of diseasediagnosed in a particular subject and/or the type of imaging modalitybeing used in conjunction with the SMSMs. The dose administered to asubject, in the context of the present invention should be sufficient toaffect a beneficial diagnostic or therapeutic response in the subject.The size of the dose also can be determined by the existence, nature,and extent of any adverse side-effects that accompany the administrationof a SMSM in a particular subject.

It is advantageous to formulate compositions in dosage unit form forease of administration and uniformity of dosage. Dosage unit form asused herein refers to physically discrete units suited as unitarydosages for the subject to be treated; each unit containing apredetermined quantity of active compound calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the uniquecharacteristics of the active compound and the particular therapeuticeffect to be achieved, and the limitations inherent in the art ofcompounding such an active compound for the treatment of individuals.Toxicity and therapeutic efficacy of such compounds can be determined byprocedures in cell cultures or experimental animals, e.g., fordetermining the LD₅₀ (the dose lethal to 50% of the population) and theED₅₀ (the dose therapeutically effective in 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex and it can be expressed as the ratio LD₅₀/ED₅₀. Compounds thatexhibit large therapeutic indices are preferred. While compounds thatexhibit toxic side effects may be used, care should be taken to design adelivery system that targets such compounds to the site of affectedtissue to minimize potential damage to uninfected cells and, thereby,reduce side effects.

Therapeutic index data obtained from cell culture assays and/or animalstudies can be used in predicting the therapeutic index in vivo andformulating a range of dosages for use in subjects, such as humansubjects. The data obtained from the cell culture assays and animalstudies can be used in formulating a range of dosage for use in humans.The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. For anycompound used in the method of the invention, the therapeuticallyeffective dose can be estimated initially from cell culture assays. Adose may be formulated in animal models to achieve a circulating plasmaconcentration range that includes the concentration of the test compoundwhich achieves a half-maximal inhibition of symptoms as determined incell culture. Such information can be used to more accurately determineuseful doses in humans. Levels in plasma may be measured, for example,by high performance liquid chromatography. Various animal models andclinical assays for evaluating effectiveness of a particular SMSM inpreventing or reducing a disease or condition are known in the art maybe used in the present invention. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized. The exact formulation, route of administration and dosage canbe chosen by the individual physician in view of the patient'scondition. (See e.g. Fingl et al, 1975, In: The Pharmacological Basis ofTherapeutics. Ch. 1 μL).

In some aspects, the SMSMs provided have a therapeutic index (LD₅₀/ED₅₀)of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600,700, 800, 900, 1000, 10000, or 100000 or more. In some aspects, theSMSMs provided have a therapeutic index (LD₅₀/ED₅₀) of at least about 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 40,50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000,10000, or 100000 or more as determined in cell culture.

In some aspects, the SMSMs provided have an IC₅₀ viability/EC₅₀ splicingvalue of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500,600, 700, 800, 900, 1000, 10000, or 100000 or more. In some aspects, theSMSMs provided have an IC₅₀ viability/EC₅₀ splicing value of at leastabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900,1000, 10000, or 100000 or more as determined in cell culture.

A dosage of using an SMSM when administered may be at least 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 grams/m² inhumans, or a dosage in another subject comparable to that in humans. Adosage (“dosage X”) of an SMSM in a subject other than a human iscomparable to a dosage (“dosage Y”) of the SMSM in humans if the serumconcentration of the scavenger in the subject post administration of theSMSM at dosage X is equal to the serum concentration of the SMSM inhumans post administration of the compound at dosage Y.

Within the scope of the present description, the effective amount of anSMSM compound or a pharmaceutically acceptable salt thereof for use inthe manufacture of a medicament, the preparation of a pharmaceutical kitor in a method for preventing and/or treating a disease in a humansubject in need thereof, is intended to include an amount in a range offrom about 1 μg to about 50 grams.

The compositions of the present invention can be administered asfrequently as necessary, including hourly, daily, weekly or monthly.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of an effective amount of an SMSM describedherein, including further embodiments in which (i) the compound isadministered once; (ii) the compound is administered to the mammalmultiple times over the span of one day; (iii) continually; or (iv)continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of an SMSM describedherein, including further embodiments in which (i) the compound isadministered continuously or intermittently: as in a single dose; (ii)the time between multiple administrations is every 6 hours; (iii) thecompound is administered to the mammal every 8 hours; (iv) the compoundis administered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of an SMSM described herein is temporarily suspended orthe dose of the compound being administered is temporarily reduced; atthe end of the drug holiday, dosing of the compound is resumed. In oneembodiment, the length of the drug holiday varies from 2 days to 1 year.

Combination Therapies

In certain instances, it is appropriate to administer at least one SMSMdescribed herein in combination with another therapeutic agent. Forexample, a compound SMSM described herein can be co-administered with asecond therapeutic agent, wherein SMSM and the second therapeutic agentmodulate different aspects of the disease, disorder or condition beingtreated, thereby providing a greater overall benefit than administrationof either therapeutic agent alone.

In some embodiments, an SMSM described herein can be used in combinationwith an anti-cancer therapy. In some embodiments, a steric modulator isused in combination with conventional chemotherapy, radiotherapy,hormonal therapy, and/or immunotherapy. In some embodiments, an SMSMdescribed herein can be used in combination with conventionalchemotherapeutic agents including alkylating agents (e.g., temozolomide,cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,mechlorethamine, uramustine, thiotepa, nitrosoureas, etc.),anti-metabolites (e.g., 5-fluorouracil, azathioprine, methotrexate,leucovorin, capecitabine, cytarabine, floxuridine, fludarabine,gemcitabine, pemetrexed, raltitrexed, etc.), plant alkaloids (e.g.,vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin,paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g.,irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate,teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin,daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin, etc.), EGFR inhibitors (e.g.,gefitinib, erlotinib, etc.), and the like.

In some embodiments, an SMSM may be administered in combination with oneor more other SMSMs.

A SMSM may be administered to a subject in need thereof prior to,concurrent with, or following the administration of chemotherapeuticagents. For instance, SMSMs may be administered to a subject at least 8hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1.5 hours,1 hour, or 30 minutes before the starting time of the administration ofchemotherapeutic agent(s). In certain embodiments, they may beadministered concurrent with the administration of chemotherapeuticagent(s). In other words, in these embodiments, SMSMs are administratedat the same time when the administration of chemotherapeutic agent(s)starts. In other embodiments, SMSMs may be administered following thestarting time of administration of chemotherapeutic agent(s) (e.g., atleast 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7hours or 8 hours after the starting time of administration ofchemotherapeutic agents). Alternatively, SMSMs may be administered atleast 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7hours or 8 hours after the completion of administration ofchemotherapeutic agents. Generally, these SMSMs are administered for asufficient period of time so that the disease or condition is preventedor reduced. Such sufficient period of time may be identical to, ordifferent from, the period during which chemotherapeutic agent(s) areadministered. In certain embodiments, multiple doses of SMSMs areadministered for each administration of a chemotherapeutic agent or acombination of multiple chemotherapeutic agents.

In certain embodiments, an appropriate dosage of a SMSM is combined witha specific timing and/or a particular route to achieve the optimumeffect in preventing or reducing the disease or condition. For instance,an SMSM may be administered to a human orally at least 1 hour, 2 hours,3 hours, 4 hours, 5 hours, 6 hours, 7 hours 8 hours, 9 hours, 10 hours,11 hours or 12 hours; or at least 1 day, 2 days, 3 days, 4 days, 5 days,6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days; or at least 1week, 2 weeks, 3 weeks or 4 weeks; or at least 1 month, 2 months, 3months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10months, 11 months or 12 months; prior to or after the beginning or thecompletion, of the administration of a chemotherapeutic agent or acombination of chemotherapeutic agents.

Subjects

The subjects that can be treated with the SMSMs and methods describedherein can be any subject that produces mRNA that is subject toalternative splicing, e.g., the subject may be a eukaryotic subject,such as a plant or an animal. In some embodiments, the subject is amammal, e.g., human. In some embodiments, the subject is a human. Insome embodiments, the subject is a non-human animal. In someembodiments, the subject is a fetus, an embryo, or a child. In someembodiments, the subject is a non-human primate such as chimpanzee, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like.

In some embodiments, the subject is prenatal (e.g., a fetus), a child(e.g., a neonate, an infant, a toddler, a preadolescent), an adolescent,a pubescent, or an adult (e.g., an early adult, a middle aged adult, asenior citizen). The human subject can be between about 0 months andabout 120 years old, or older. The human subject can be between about 0and about 12 months old; for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 months old. The human subject can be between about 0 and12 years old; for example, between about 0 and 30 days old; betweenabout 1 month and 12 months old; between about 1 year and 3 years old;between about 4 years and 5 years old; between about 4 years and 12years old; about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years old. Thehuman subject can be between about 13 years and 19 years old; forexample, about 13, 14, 15, 16, 17, 18, or 19 years old. The humansubject can be between about 20 and about 39 year old; for example,about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, or 39 years old. The human subject can be between about 40to about 59 years old; for example, about 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 years old. Thehuman subject can be greater than 59 years old; for example, about 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,112, 113, 114, 115, 116, 117, 118, 119, or 120 years old. The humansubjects can include living subjects or deceased subjects. The humansubjects can include male subjects and/or female subjects.

Assays

Gene expression experiments often involve measuring the relative amountof gene expression products, such as mRNA, expressed in two or moreexperimental conditions. This is because altered levels of a specificsequence of a gene expression product can suggest a changed need for theprotein coded for by the gene expression product, perhaps indicating ahomeostatic response or a pathological condition.

In some embodiments, a method can comprise measuring, assaying orobtaining expression levels of one or more genes. In some cases, themethod provides a number or a range of numbers, of genes that theexpression levels of the genes can be used to diagnose, characterize orcategorize a biological sample. In some embodiments, the gene expressiondata corresponds to data of an expression level of one or morebiomarkers that are related to a disease or condition. The number ofgenes used can be between about 1 and about 500; for example about1-500, 1-400, 1-300, 1-200, 1-100, 1-50, 1-25, 1-10, 10-500, 10-400,10-300, 10-200, 10-100, 10-50, 10-25, 25-500, 25-400, 25-300, 25-200,25-100, 25-50, 50-500, 50-400, 50-300, 50-200, 50-100, 100-500, 100-400,100-300, 100-200, 200-500, 200-400, 200-300, 300-500, 300-400, 400-500,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80,85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210,220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350,360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490,500, or any included range or integer. For example, at least about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 33, 35, 38, 40, 43, 45, 48, 50,53, 58, 63, 65, 68, 100, 120, 140, 142, 145, 147, 150, 152, 157, 160,162, 167, 175, 180, 185, 190, 195, 200, 300, 400, 500 or more totalgenes can be used. The number of genes used can be less than or equal toabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 33, 35, 38, 40, 43,45, 48, 50, 53, 58, 63, 65, 68, 100, 120, 140, 142, 145, 147, 150, 152,157, 160, 162, 167, 175, 180, 185, 190, 195, 200, 300, 400, 500, ormore.

In some embodiments, relative gene expression, as compared to normalcells and/or tissues of the same organ, can be determined by measuringthe relative rates of transcription of RNA, such as by production ofcorresponding cDNAs and then analyzing the resulting DNA using probesdeveloped from the gene sequences as corresponding to a genetic marker.Thus, the levels of cDNA produced by use of reverse transcriptase withthe full RNA complement of a cell suspected of being cancerous producesa corresponding amount of cDNA that can then be amplified usingpolymerase chain reaction, or some other means, such as linearamplification, isothermal amplification, NASB, or rolling circleamplification, to determine the relative levels of resulting cDNA and,thereby, the relative levels of gene expression. General methods fordetermining gene expression product levels are known to the art and mayinclude but are not limited to one or more of the following: additionalcytological assays, assays for specific proteins or enzyme activities,assays for specific expression products including protein or RNA orspecific RNA splice variants, in situ hybridization, whole or partialgenome expression analysis, microarray hybridization assays, SAGE,enzyme linked immuno-absorbance assays, mass-spectrometry,immuno-histochemistry, blotting, microarray, RT-PCR, quantitative PCR,sequencing, RNA sequencing, DNA sequencing (e.g., sequencing of cDNAobtained from RNA); Next-Gen sequencing, nanopore sequencing,pyrosequencing, or Nanostring sequencing. Gene expression product levelsmay be normalized to an internal standard such as total mRNA or theexpression level of a particular gene including but not limited toglyceraldehyde 3-phosphate dehydrogenase, or tubulin.

Gene expression data generally comprises the measurement of the activity(or the expression) of a plurality of genes, to create a picture ofcellular function. Gene expression data can be used, for example, todistinguish between cells that are actively dividing, or to show how thecells react to a particular treatment. Microarray technology can be usedto measure the relative activity of previously identified target genesand other expressed sequences. Sequence based techniques, like serialanalysis of gene expression (SAGE, SuperSAGE) are also used forassaying, measuring or obtaining gene expression data. SuperSAGE isespecially accurate and can measure any active gene, not just apredefined set. In an RNA, mRNA or gene expression profiling microarray,the expression levels of thousands of genes can be simultaneouslymonitored to study the effects of certain treatments, diseases, anddevelopmental stages on gene expression.

In accordance with the foregoing, the expression level of a gene,marker, gene expression product, mRNA, pre-mRNA, or a combinationthereof may be determined using northern blotting and employing thesequences as identified herein to develop probes for this purpose. Suchprobes may be composed of DNA or RNA or synthetic nucleotides or acombination of these and may advantageously be comprised of a contiguousstretch of nucleotide residues matching, or complementary to, a sequencecorresponding to a genetic marker. Such probes will most usefullycomprise a contiguous stretch of at least 15-200 residues or moreincluding 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 80, 85, 90, 95, 100, 110, 120,130, 140, 150, 160, 175, or 200 nucleotides or more. Thus, where asingle probe binds multiple times to the transcriptome of experimentalcells, whereas binding of the same probe to a similar amount oftranscriptome derived from the genome of control cells of the same organor tissue results in observably more or less binding, this is indicativeof differential expression of a gene, marker, gene expression product,mRNA, or pre-mRNA comprising, or corresponding to, sequencescorresponding to a genetic marker from which the probe sequence wasderived.

In some embodiments of the present invention, gene expression may bedetermined by microarray analysis using, for example, Affymetrix arrays,cDNA microarrays, oligonucleotide microarrays, spotted microarrays, orother microarray products from Biorad, Agilent, or Eppendorf.Microarrays provide particular advantages because they may contain alarge number of genes or alternative splice variants that may be assayedin a single experiment. In some cases, the microarray device may containthe entire human genome or transcriptome or a substantial fractionthereof allowing a comprehensive evaluation of gene expression patterns,genomic sequence, or alternative splicing. Markers may be found usingstandard molecular biology and microarray analysis techniques asdescribed in Sambrook Molecular Cloning a Laboratory Manual 2001 andBaldi, P., and Hatfield, W. G., DNA Microarrays and Gene Expression2002.

Microarray analysis generally begins with extracting and purifyingnucleic acid from a biological sample, (e.g. a biopsy or fine needleaspirate) using methods known to the art. For expression and alternativesplicing analysis it may be advantageous to extract and/or purify RNAfrom DNA. It may further be advantageous to extract and/or purify mRNAfrom other forms of RNA such as tRNA and rRNA. In some embodiments, RNAsamples with RIN are typically not used for multi-gene microarrayanalysis, and may instead be used only for single-gene RT-PCR and/orTaqMan assays. Microarray, RT-PCR and TaqMan assays are standardmolecular techniques well known in the relevant art. TaqMan probe-basedassays are widely used in real-time PCR including gene expressionassays, DNA quantification and SNP genotyping.

Various kits can be used for the amplification of nucleic acid and probegeneration of the subject methods. In some embodiments, AmbionWT-expression kit can be used. Ambion WT-expression kit allowsamplification of total RNA directly without a separate ribosomal RNA(rRNA) depletion step. With the Ambion® WT Expression Kit, samples assmall as 50 ng of total RNA can be analyzed on Affymetrix® GeneChip®Human, Mouse, and Rat Exon and Gene 1.0 ST Arrays. In addition to thelower input RNA requirement and high concordance between the Affymetrix®method and TaqMan® real-time PCR data, the Ambion® WT Expression Kitprovides a significant increase in sensitivity. For example, a greaternumber of probe sets detected above background can be obtained at theexon level with the Ambion® WT Expression Kit as a result of anincreased signal-to-noise ratio. Ambion WT-expression kit may be used incombination with additional Affymetrix labeling kit.

In some embodiments, AmpTec Trinucleotide Nano mRNA Amplification kit(6299-A15) can be used in the subject methods. The ExpressArt®TRinucleotide mRNA amplification Nano kit is suitable for a wide range,from 1 ng to 700 ng of input total RNA. According to the amount of inputtotal RNA and the required yields of a RNA, it can be used for 1-round(input >300 ng total RNA) or 2-rounds (minimal input amount 1 ng totalRNA), with a RNA yields in the range of >10 μg. AmpTec's proprietaryTRinucleotide priming technology results in preferential amplificationof mRNAs (independent of the universal eukaryotic 3′-poly(A)-sequence),combined with selection against rRNAs. This kit can be used incombination with cDNA conversion kit and Affymetrix labeling kit.

In some embodiments, gene expression levels can be obtained or measuredin an individual without first obtaining a sample. For example, geneexpression levels may be determined in vivo, that is in the individual.Methods for determining gene expression levels in vivo are known to theart and include imaging techniques such as CAT, MRI; NMR; PET; andoptical, fluorescence, or biophotonic imaging of protein or RNA levelsusing antibodies or molecular beacons. Such methods are described in US2008/0044824, US 2008/0131892, herein incorporated by reference.Additional methods for in vivo molecular profiling are contemplated tobe within the scope of the present invention.

Provided herein are methods for determining whether an SMSM compound ora pharmaceutically acceptable salt thereof modulates the amount of one,two, three or more RNA transcripts (e.g., pre-mRNA or mRNA transcriptsor isoforms thereof) of one, two, three or more genes.

In one embodiment, provided herein is a method for determining whetheran SMSM compound or a pharmaceutically acceptable salt thereof modulatesthe amount of an RNA transcript, comprising: (a) contacting a cell withan SMSM compound or a pharmaceutically acceptable salt thereof, and (b)determining the amount of the RNA transcript produced by the cell,wherein an alteration in the amount of the RNA transcript in thepresence of an SMSM compound or a pharmaceutically acceptable saltthereof relative to the amount of the RNA transcript in the absence ofan SMSM compound or a pharmaceutically acceptable salt thereof or thepresence of a negative control (e.g., a vehicle control such as PBS orDMSO) indicates that an SMSM compound or a pharmaceutically acceptablesalt thereof modulates the amount of the RNA transcript. In someembodiments, provided herein is a method for determining whether an SMSMcompound or a pharmaceutically acceptable salt thereof modulates theamount of an RNA transcript (e.g., an mRNA transcript), comprising: (a)contacting a first cell with an SMSM compound or a pharmaceuticallyacceptable salt thereof, (b) contacting a second cell with a negativecontrol (e.g., a vehicle control, such as PBS or DMSO); and (c)determining the amount of the RNA transcript produced by the first celland the second cell; and (d) comparing the amount of the RNA transcriptproduced by the first cell to the amount of the RNA transcript expressedby the second cell, wherein an alteration in the amount of the RNAtranscript produced by the first cell relative to the amount of the RNAtranscript produced by the second cell indicates that an SMSM compoundor a pharmaceutically acceptable salt thereof modulates the amount ofthe RNA transcript. In some embodiments, the contacting of the cell withthe compound occurs in cell culture. In other embodiments, thecontacting of the cell with the compound occurs in a subject, such as anon-human animal subject. In some embodiments, provided herein is amethod for determining whether an SMSM compound or a pharmaceuticallyacceptable salt thereof modulates the splicing of an RNA transcript(e.g., an mRNA transcript), comprising: (a) culturing a cell in thepresence of an SMSM compound or a pharmaceutically acceptable saltthereof; and (b) determining the amount of the two or more RNAtranscripts splice variants produced by the cell, wherein an alterationin the amount of the two or more RNA transcripts in the presence of thecompound relative to the amount of the two or more RNA transcriptssplice variants in the absence of the compound or the presence of anegative control (e.g., a vehicle control such as PBS or DMSO) indicatesthat an SMSM compound or a pharmaceutically acceptable salt thereofmodulates the splicing of the RNA transcript.

In some embodiments, provided herein is a method for determining whetheran SMSM compound or a pharmaceutically acceptable salt thereof modulatesthe splicing of an RNA transcript (e.g., an mRNA transcript),comprising: (a) culturing a cell in the presence of an SMSM compound ora pharmaceutically acceptable salt thereof; (b) isolating two or moreRNA transcript splice variants from the cell after a certain period oftime; and (c) determining the amount of the two or more RNA transcriptsplice variants produced by the cell, wherein an alteration in theamount of the two or more RNA transcript in the presence of the compoundrelative to the amount of the two or more RNA transcript splice variantsin the absence of the compound or the presence of a negative control(e.g., a vehicle control such as PBS or DMSO) indicates that an SMSMcompound or a pharmaceutically acceptable salt thereof modulates thesplicing of the RNA transcript. In some embodiments, provided herein isa method for determining whether an SMSM compound or a pharmaceuticallyacceptable salt thereof modulates the splicing of an RNA transcript(e.g., an mRNA transcript), comprising (a) culturing a first cell in thepresence of an SMSM compound or a pharmaceutically acceptable saltthereof; (b) culturing a second cell in the presence of a negativecontrol (e.g., a vehicle control, such as PBS or DMSO); (c) isolatingtwo or more RNA transcript splice variants produced by the first celland isolating two or more RNA transcript splice variants produced by thesecond cell; (d) determining the amount of the two or more RNAtranscript splice variants produced by the first cell and the secondcell; and (e) comparing the amount of the two or more RNA transcriptsplice variants produced by the first cell to the amount of the two ormore RNA transcript splice variants produced by the second cell, whereinan alteration in the amount of the two or more RNA transcript splicevariants produced by the first cell relative to the amount of the two ormore RNA transcript splice variants produced by the second cellindicates that an SMSM compound or a pharmaceutically acceptable saltthereof modulates the splicing of the RNA transcript.

In some embodiments, provided herein is a method for determining whetheran SMSM compound or a pharmaceutically acceptable salt thereof modulatesthe amount of an RNA transcript (e.g., an mRNA transcript), comprising:(a) contacting a cell-free system with an SMSM compound or apharmaceutically acceptable salt thereof, and (b) determining the amountof the RNA transcript produced by the cell-free system, wherein analteration in the amount of the RNA transcript in the presence of thecompound relative to the amount of the RNA transcript in the absence ofthe compound or the presence of a negative control (e.g., a vehiclecontrol such as PBS or DMSO) indicates that an SMSM compound or apharmaceutically acceptable salt thereof modulates the amount of the RNAtranscript. In some embodiments, provided herein is a method fordetermining whether an SMSM compound or a pharmaceutically acceptablesalt thereof modulates the amount of an RNA transcript (e.g., an mRNAtranscript), comprising: (a) contacting a first cell-free system with anSMSM compound or a pharmaceutically acceptable salt thereof, (b)contacting a second cell-free system with a negative control (e.g., avehicle control, such as PBS or DMSO); and (c) determining the amount ofthe RNA transcript produced by the first cell-free system and the secondcell-free system; and (d) comparing the amount of the RNA transcriptproduced by the first cell-free system to the amount of the RNAtranscript expressed by the second cell-free system, wherein analteration in the amount of the RNA transcript produced by the firstcell-free system relative to the amount of the RNA transcript producedby the second cell-free system indicates that an SMSM compound or apharmaceutically acceptable salt thereof modulates the amount of the RNAtranscript. In some embodiments, the cell-free system comprises purelysynthetic RNA, synthetic or recombinant (purified) enzymes, and proteinfactors. In other embodiments, the cell-free system comprises RNAtranscribed from a synthetic DNA template, synthetic or recombinant(purified) enzymes, and protein factors. In other embodiments, thecell-free system comprises purely synthetic RNA and nuclear extract. Inother embodiments, the cell-free system comprises RNA transcribed from asynthetic DNA template and nuclear extract. In other embodiments, thecell-free system comprises purely synthetic RNA and whole cell extract.In other embodiments, the cell-free system comprises RNA transcribedfrom a synthetic DNA template and whole cell extract. In someembodiments, the cell-free system additionally comprises regulatory RNAs(e.g., microRNAs).

In some embodiments, provided herein is a method for determining whetheran SMSM compound or a pharmaceutically acceptable salt thereof modulatesthe splicing of an RNA transcript (e.g., an mRNA transcript),comprising: (a) contacting a cell-free system with an SMSM compound or apharmaceutically acceptable salt thereof; and (b) determining the amountof two or more RNA transcript splice variants produced by the cell-freesystem, wherein an alteration in the amount of the two or more RNAtranscript splice variants in the presence of the compound relative tothe amount of the two or more RNA transcript splice variants in theabsence of the compound or the presence of a negative control (e.g., avehicle control such as PBS or DMSO) indicates that an SMSM compound ora pharmaceutically acceptable salt thereof modulates the splicing of theRNA transcript. In some embodiments, provided herein is a method fordetermining whether an SMSM compound or a pharmaceutically acceptablesalt thereof modulates the splicing of an RNA transcript (e.g., an mRNAtranscript), comprising: (a) contacting a first cell-free system with anSMSM compound or a pharmaceutically acceptable salt thereof; (b)contacting a second cell-free system with a negative control (e.g., avehicle control, such as PBS or DMSO); and (c) determining the amount oftwo or more RNA transcript splice variants produced by the firstcell-free system and the second cell-free system; and (d) comparing theamount of the two or more RNA transcript splice variants produced by thefirst cell-free system to the amount of the RNA transcript expressed bythe second cell-free system, wherein an alteration in the amount of thetwo or more RNA transcript splice variants produced by the firstcell-free system relative to the amount of the two or more RNAtranscript splice variants produced by the second cell-free systemindicates that an SMSM compound or a pharmaceutically acceptable saltthereof modulates the splicing of the RNA transcript. In someembodiments, the cell-free system comprises purely synthetic RNA,synthetic or recombinant (purified) enzymes, and protein factors. Inother embodiments, the cell-free system comprises RNA transcribed from asynthetic DNA template, synthetic or recombinant (purified) enzymes, andprotein factors. In other embodiments, the cell-free system comprisespurely synthetic RNA and nuclear extract. In other embodiments, thecell-free system comprises RNA transcribed from a synthetic DNA templateand nuclear extract. In other embodiments, the cell-free systemcomprises purely synthetic RNA and whole cell extract. In otherembodiments, the cell-free system comprises RNA transcribed from asynthetic DNA template and whole cell extract. In some embodiments, thecell-free system additionally comprises regulatory RNAs (e.g.,microRNAs).

In some embodiments, provided herein is a method for determining whetheran SMSM compound or a pharmaceutically acceptable salt thereof modulatesthe amount of an RNA transcript (e.g., an mRNA transcript), comprising:(a) culturing a cell in the presence of an SMSM compound or apharmaceutically acceptable salt thereof, (b) isolating the RNAtranscript from the cell after a certain period of time; and (c)determining the amount of the RNA transcript produced by the cell,wherein an alteration in the amount of the RNA transcript in thepresence of the compound relative to the amount of the RNA transcript inthe absence of the compound or the presence of a negative control (e.g.,a vehicle control such as PBS or DMSO) indicates that an SMSM compoundor a pharmaceutically acceptable salt thereof modulates the amount ofthe RNA transcript. In some embodiments, provided herein is a method fordetermining whether an SMSM compound or a pharmaceutically acceptablesalt thereof modulates the amount of an RNA transcript (e.g., an mRNAtranscript), comprising (a) culturing a first cell in the presence of anSMSM compound or a pharmaceutically acceptable salt thereof, (b)culturing a second cell in the presence of a negative control (e.g., avehicle control, such as PBS or DMSO); (c) isolating the RNA transcriptproduced by the first cell and isolating the RNA transcript produced bythe second cell; (d) determining the amount of the RNA transcriptproduced by the first cell and the second cell; and (e) comparing theamount of the RNA transcript produced by the first cell to the amount ofthe RNA transcript produced by the second cell, wherein an alteration inthe amount of the RNA transcript produced by the first cell relative tothe amount of the RNA transcript produced by the second cell indicatesthat an SMSM compound or a pharmaceutically acceptable salt thereofmodulates the amount of the RNA transcript.

In some embodiments, the cell contacted or cultured with an SMSMcompound or a pharmaceutically acceptable salt thereof is a primary cellfrom a subject. In some embodiments, the cell contacted or cultured withan SMSM compound or a pharmaceutically acceptable salt thereof is aprimary cell from a subject with a disease. In specific embodiments, thecell contacted or cultured with an SMSM compound or a pharmaceuticallyacceptable salt thereof is a primary cell from a subject with a diseaseassociated with an aberrant amount of an RNA transcript for a particulargene. In some specific embodiments, the cell contacted or cultured withan SMSM compound or a pharmaceutically acceptable salt thereof is aprimary cell from a subject with a disease associated with an aberrantamount of an isoform of a particular gene. In some embodiments, the cellcontacted or cultured with an SMSM compound or a pharmaceuticallyacceptable salt thereof is a fibroblast, an immune cell, or a musclecell. In some embodiments, the cell contacted or cultured with an SMSMcompound or a pharmaceutically acceptable salt thereof is a diseasedcell.

In some embodiments, the cell contacted or cultured with an SMSMcompound or a pharmaceutically acceptable salt thereof is from a cellline. In some embodiments, the cell contacted or cultured with an SMSMcompound or a pharmaceutically acceptable salt thereof is a cell linederived from a subject with a disease. In some embodiments, the cellcontacted or cultured with an SMSM compound or a pharmaceuticallyacceptable salt thereof is from a cell line known to have aberrant RNAtranscript levels for a particular gene. In specific embodiments, thecell contacted or cultured with an SMSM compound or a pharmaceuticallyacceptable salt thereof is from a cell line derived from a subject witha disease known to have aberrant RNA transcript levels for a particulargene. In some embodiments, the cell contacted or cultured with an SMSMcompound or a pharmaceutically acceptable salt thereof is a diseasedcell line. In some specific embodiments, the cell contacted or culturedwith an SMSM compound or a pharmaceutically acceptable salt thereof isfrom a cell line derived from a subject with a disease known to have anaberrant amount of an RNA isoform and/or protein isoform of a particulargene. Non-limiting examples of cell lines include 293, 3T3, 4T1, 721,9L, A2780, A172, A20, A253, A431, A-549, A-673, ALC, B 16, B35, BCP-1,BEAS-2B, bEnd.3, BHK, BR 293, BT20, BT483, BxPC3, C₂-C_(12,) C₃h-10T1/2, C6/36, C6, Cal-27, CHO, COR-L23, COS, COV-434, CML Tl, CMT,CRL7030, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299,H69, HB54, HB55, HCA2, HEK-293, HeLa, Hepalclc7, HL-60, HMEC, Hs578T,HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22,KG1, KYO1, LNCap, Ma-Mel, MC-38, MCF-7, MCF-IOA, MDA-MB-231, MDA-MB-468,MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69,NIH-3T3, NALM-1, NSO, NW-145, OPCN, OPCT, PNT-1A, PNT-2, Raji, RBL,RenCa, RIN-5F, RMA, Saos-2, Sf21, Sf9, SiHa, SKBR3, SKOV-3, T2, T-47D,T84, THP1, U373, U87, U937, VCaP, Vero, VERY, W138, WM39, WT-49, X63,YAC-1, and YAR cells. In one embodiment, the cells are from a patient.

In some embodiments, a dose-response assay is performed. In oneembodiment, the dose response assay comprises: (a) contacting a cellwith a concentration of an SMSM compound or a pharmaceuticallyacceptable salt thereof; (b) determining the amount of the RNAtranscript produced by the cell, wherein an alteration in the amount ofthe RNA transcript in the presence of the compound relative to theamount of the RNA transcript in the absence of the compound or thepresence of a negative control (e.g., a vehicle control such as PBS orDMSO) indicates that an SMSM compound or a pharmaceutically acceptablesalt thereof modulates the amount of the RNA transcript; (c) repeatingsteps (a) and (b), wherein the only experimental variable changed is theconcentration of the compound or a form thereof, and (d) comparing theamount of the RNA transcript produced at the different concentrations ofthe compound or a form thereof. In some embodiments, the dose responseassay comprises: (a) culturing a cell in the presence of an SMSMcompound or a pharmaceutically acceptable salt thereof, (b) isolatingthe RNA transcript from the cell after a certain period of time; (c)determining the amount of the RNA transcript produced by the cell,wherein an alteration in the amount of the RNA transcript in thepresence of the compound relative to the amount of the RNA transcript inthe absence of the compound or the presence of a negative control (e.g.,a vehicle control such as PBS or DMSO) indicates that an SMSM compoundor a pharmaceutically acceptable salt thereof modulates the amount ofthe RNA transcript; (d) repeating steps (a), (b), and (c), wherein theonly experimental variable changed is the concentration of the compoundor a form thereof, and (e) comparing the amount of the RNA transcriptproduced at the different concentrations of the compound or a formthereof. In some embodiments, the dose-response assay comprises: (a)contacting each well of a microtiter plate containing cells with adifferent concentration of an SMSM compound or a pharmaceuticallyacceptable salt thereof; (b) determining the amount of an RNA transcriptproduced by cells in each well; and (c) assessing the change of theamount of the RNA transcript at the different concentrations of thecompound or form thereof.

In some embodiments described herein, the cell is contacted or culturedwith an SMSM compound or a pharmaceutically acceptable salt thereof, ora tissue sample is contacted with an SMSM compound or a pharmaceuticallyacceptable salt thereof, or a negative control for a period of 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72hours or more. In other embodiments described herein, the cell iscontacted or cultured with an SMSM compound or a pharmaceuticallyacceptable salt thereof, or a tissue sample is contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof, or a negativecontrol for a period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4hours, 6 to 12 hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24to 48 hours, 48 to 72 hours.

In some embodiments described herein, the cell is contacted or culturedwith a concentration of an SMSM compound or a pharmaceuticallyacceptable salt thereof, or a tissue sample is contacted with aconcentration of an SMSM compound or a pharmaceutically acceptable saltthereof, wherein the concentration is 0.01 μM, 0.05 μM, 1 μM, 2 μM, 5μM, 10 μM, 15 μM, 20 μM, 25 μM, 50 μM, 75 μM, 100 μM, or 150 μM. Inother embodiments described herein, the cell is contacted or culturedwith concentration of an SMSM compound or a pharmaceutically acceptablesalt thereof, or a tissue sample is contacted with a concentration of anSMSM compound or a pharmaceutically acceptable salt thereof, wherein theconcentration is 175 μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 μM,450 μM, 500 μM, 550 μM, 600 μM, 650 μM, 700 μM, 750 μM, 800 μM, 850 μM,900 μM, 950 μM or 1 mM. In some embodiments described herein, the cellis contacted or cultured with concentration of an SMSM compound or apharmaceutically acceptable salt thereof, or a tissue sample iscontacted with a concentration of an SMSM compound or a pharmaceuticallyacceptable salt thereof, wherein the concentration is 5 nM, 10 nM, 20nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, or 950 nM. In someembodiments described herein, the cell is contacted or cultured withconcentration of an SMSM compound or a pharmaceutically acceptable saltthereof, or a tissue sample is contacted with a concentration of an SMSMcompound or a pharmaceutically acceptable salt thereof, wherein theconcentration is between 0.01 μM to 0.1 μM, 0.1 μM to 1 μM, 1 μM to 50μM, 50 μM to 100 μM, 100 μM to 500 μM, 500 μM to 1 nM, 1 nM to 10 nM, 10nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM.

Techniques known to one skilled in the art may be used to determine theamount of an RNA transcript. In some embodiments, the amount of one,two, three or more RNA transcripts is measured using deep sequencing,such as ILLUMINA® RNASeq, ILLUMINA® next generation sequencing (NGS),ION TORRENT™ RNA next generation sequencing, 454™ pyrosequencing, orSequencing by Oligo Ligation Detection (SOLID™). In other embodiments,the amount of multiple RNA transcripts is measured using an exon array,such as the GENECHIP® human exon array. In some embodiments, the amountof one, two, three or more RNA transcripts is determined by RT-PCR. Inother embodiments, the amount of one, two, three or more RNA transcriptsis measured by RT-qPCR. Techniques for conducting these assays are knownto one skilled in the art.

In some embodiments, a statistical analysis or other analysis isperformed on data from the assay utilized to measure an RNA transcript.In some embodiments, a student t-test statistical analysis is performedon data from the assay utilized to measure an RNA transcript todetermine those RNA transcripts that have an alternation in amount inthe presence of the compound relative to the amount in the absence ofthe compound or presence of a negative control. In specific embodiments,the student t-test value of those RNA transcripts with the alternationis 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%. In some specific embodiments,p value of those RNA transcripts with the alternation is 10%, 5%, 4%,3%, 2%, 1%, 0.5% or 0.1%. In certain specific embodiments, the studentt-test and p values of those RNA transcripts with the alteration are10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% and 10%, 5%, 4%, 3%, 2%, 1%, 0.5%or 0.1%), respectively.

In some embodiments, a further analysis is performed to determine how anSMSM compound or a pharmaceutically acceptable salt thereof is changingthe amount of an RNA transcript. In specific embodiments, a furtheranalysis is performed to determine if an alternation in the amount of anRNA transcript in the presence of an SMSM compound or a pharmaceuticallyacceptable salt thereof relative the amount of the RNA transcript in theabsence of the compound or a form thereof, or the presence of a negativecontrol is due to changes in transcription, splicing, and/or stabilityof the RNA transcript. Techniques known to one skilled in the art may beused to determine whether an SMSM compound or a pharmaceuticallyacceptable salt thereof changes, e.g., the transcription, splicingand/or stability of an RNA transcript.

In some embodiments, the stability of one or more RNA transcripts isdetermined by serial analysis of gene expression (SAGE), differentialdisplay analysis (DD), RNA arbitrarily primer (RAP)-PCR, restrictionendonuclease-lytic analysis of differentially expressed sequences(READS), amplified restriction fragment-length polymorphism (ALFP),total gene expression analysis (TOGA), RT-PCR, RT-qPCR, high-densitycDNA filter hybridization analysis (HDFCA), suppression subtractivehybridization (SSH), differential screening (DS), cDNA arrays,oligonucleotide chips, or tissue microarrays. In other embodiments, thestability of one or more RNA transcripts is determined by Northernblots, RNase protection, or slot blots.

In some embodiments, the transcription in a cell or tissue sample isinhibited before (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36hours, 48 hours, or 72 hours before) or after (e.g., 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours after) thecell or the tissue sample is contacted or cultured with an inhibitor oftranscription, such as a-amanitin, DRB, flavopiridol, triptolide, oractinomycin-D. In other embodiments, the transcription in a cell ortissue sample is inhibited with an inhibitor of transcription, such asα-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D, while thecell or tissue sample is contacted or cultured with an SMSM compound ora pharmaceutically acceptable salt thereof.

In some embodiments, the level of transcription of one or more RNAtranscripts is determined by nuclear run-on assay or an in vitrotranscription initiation and elongation assay. In some embodiments, thedetection of transcription is based on measuring radioactivity orfluorescence. In some embodiments, a PCR-based amplification step isused.

In some embodiments, the amount of alternatively spliced forms of theRNA transcripts of a particular gene are measured to see if there is analteration in the amount of one, two or more alternatively spliced formsof the RNA transcripts of the gene. In some embodiments, the amount ofan isoform encoded by a particular gene is measured to see if there isan alteration in the amount of the isoform. In some embodiments, thelevels of spliced forms of RNA are quantified by RT-PCR, RT-qPCR, ornorthern blotting. In other embodiments, sequence-specific techniquesmay be used to detect the levels of an individual splice form. In someembodiments, splicing is measured in vitro using nuclear extracts. Insome embodiments, detection is based on measuring radioactivity orfluorescence. Techniques known to one skilled in the art may be used tomeasure alterations in the amount of alternatively spliced forms of anRNA transcript of a gene and alterations in the amount of an isoformencoded by a gene.

Biological Samples

A sample, e.g., a biological sample can be taken from a subject andexamined to determine whether the subject produces mRNA that is subjectto alternative splicing. A biological sample can comprise a plurality ofbiological samples. The plurality of biological samples can contain twoor more biological samples; for examples, about 2-1000, 2-500, 2-250,2-100, 2-75, 2-50, 2-25, 2-10, 10-1000, 10-500, 10-250, 10-100, 10-75,10-50, 10-25, 25-1000, 25-500, 25-250, 25-100, 25-75, 25-50, 50-1000,50-500, 50-250, 50-100, 50-75, 60-70, 100-1000, 100-500, 100-250,250-1000, 250-500, 500-1000, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 90, 95, 100,110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240,250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650,700, 750, 800, 850, 900, 950, 1000, or more biological samples. Thebiological samples can be obtained from a plurality of subjects, givinga plurality of sets of a plurality of samples. The biological samplescan be obtained from about 2 to about 1000 subjects, or more; forexample, about 2-1000, 2-500, 2-250, 2-100, 2-50, 2-25, 2-20, 2-10,10-1000, 10-500, 10-250, 10-100, 10-50, 10-25, 10-20, 15-20, 25-1000,25-500, 25-250, 25-100, 25-50, 50-1000, 50-500, 50-250, 50-100,100-1000, 100-500, 100-250, 250-1000, 250-500, 500-1000, or at least 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 68, 70, 75, 80, 85, 90, 95,100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230,240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600,650, 700, 750, 800, 850, 900, 950, to 1000 or more subjects.

The biological samples can be obtained from human subjects. Thebiological samples can be obtained from human subjects at differentages. The human subject can be prenatal (e.g., a fetus), a child (e.g.,a neonate, an infant, a toddler, a preadolescent), an adolescent, apubescent, or an adult (e.g., an early adult, a middle aged adult, asenior citizen). The human subject can be between about 0 months andabout 120 years old, or older. The human subject can be between about 0and about 12 months old; for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 months old. The human subject can be between about 0 and12 years old; for example, between about 0 and 30 days old; betweenabout 1 month and 12 months old; between about 1 year and 3 years old;between about 4 years and 5 years old; between about 4 years and 12years old; about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years old. Thehuman subject can be between about 13 years and 19 years old; forexample, about 13, 14, 15, 16, 17, 18, or 19 years old. The humansubject can be between about 20 and about 39 year old; for example,about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, or 39 years old. The human subject can be between about 40to about 59 years old; for example, about 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 years old. Thehuman subject can be greater than 59 years old; for example, about 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,112, 113, 114, 115, 116, 117, 118, 119, or 120 years old. The humansubjects can include living subjects or deceased subjects. The humansubjects can include male subjects and/or female subjects.

Biological samples can be obtained from any suitable source that allowsdetermination of expression levels of genes, e.g., from cells, tissues,bodily fluids or secretions, or a gene expression product derivedtherefrom (e.g., nucleic acids, such as DNA or RNA; polypeptides, suchas protein or protein fragments). The nature of the biological samplecan depend upon the nature of the subject. If a biological sample isfrom a subject that is a unicellular organism or a multicellularorganism with undifferentiated tissue, the biological sample cancomprise cells, such as a sample of a cell culture, an excision of theorganism, or the entire organism. If a biological sample is from amulticellular organism, the biological sample can be a tissue sample, afluid sample, or a secretion.

The biological samples can be obtained from different tissues. The termtissue is meant to include ensembles of cells that are of a commondevelopmental origin and have similar or identical function. The termtissue is also meant to encompass organs, which can be a functionalgrouping and organization of cells that can have different origins. Thebiological sample can be obtained from any tissue. Suitable tissues froma plant can include, but are not limited to, epidermal tissue such asthe outer surface of leaves; vascular tissue such as the xylem andphloem, and ground tissue. Suitable plant tissues can also includeleaves, roots, root tips, stems, flowers, seeds, cones, shoots, stobili,pollen, or a portion or combination thereof.

The biological samples can be obtained from different tissue samplesfrom one or more humans or non-human animals. Suitable tissues caninclude connective tissues, muscle tissues, nervous tissues, epithelialtissues or a portion or combination thereof. Suitable tissues can alsoinclude all or a portion of a lung, a heart, a blood vessel (e.g.,artery, vein, capillary), a salivary gland, a esophagus, a stomach, aliver, a gallbladder, a pancreas, a colon, a rectum, an anus, ahypothalamus, a pituitary gland, a pineal gland, a thyroid, aparathyroid, an adrenal gland, a kidney, a ureter, a bladder, a urethra,a lymph node, a tonsil, an adenoid, a thymus, a spleen, skin, muscle, abrain, a spinal cord, a nerve, an ovary, a fallopian tube, a uterus,vaginal tissue, a mammary gland, a testicle, a vas deferens, a seminalvesicle, a prostate, penile tissue, a pharynx, a larynx, a trachea, abronchi, a diaphragm, bone marrow, a hair follicle, or a combinationthereof. A biological sample from a human or non-human animal can alsoinclude a bodily fluid, secretion, or excretion; for example, abiological sample can be a sample of aqueous humour, vitreous humour,bile, blood, blood serum, breast milk, cerebrospinal fluid, endolymph,perilymph, female ejaculate, amniotic fluid, gastric juice, menses,mucus, peritoneal fluid, pleural fluid, saliva, sebum, semen, sweat,tears, vaginal secretion, vomit, urine, feces, or a combination thereof.The biological sample can be from healthy tissue, diseased tissue,tissue suspected of being diseased, or a combination thereof.

In some embodiments, the biological sample is a fluid sample, forexample a sample of blood, serum, sputum, urine, semen, or otherbiological fluid. In certain embodiments the sample is a blood sample.In some embodiments the biological sample is a tissue sample, such as atissue sample taken to determine the presence or absence of disease inthe tissue. In certain embodiments the sample is a sample of thyroidtissue.

The biological samples can be obtained from subjects in different stagesof disease progression or different conditions. Different stages ofdisease progression or different conditions can include healthy, at theonset of primary symptom, at the onset of secondary symptom, at theonset of tertiary symptom, during the course of primary symptom, duringthe course of secondary symptom, during the course of tertiary symptom,at the end of the primary symptom, at the end of the secondary symptom,at the end of tertiary symptom, after the end of the primary symptom,after the end of the secondary symptom, after the end of the tertiarysymptom, or a combination thereof. Different stages of diseaseprogression can be a period of time after being diagnosed or suspectedto have a disease; for example, at least about, or at least, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or24 hours; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days; 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks; 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11 or 12 months; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49or 50 years after being diagnosed or suspected to have a disease.Different stages of disease progression or different conditions caninclude before, during or after an action or state; for example,treatment with drugs, treatment with a surgery, treatment with aprocedure, performance of a standard of care procedure, resting,sleeping, eating, fasting, walking, running, performing a cognitivetask, sexual activity, thinking, jumping, urinating, relaxing, beingimmobilized, being emotionally traumatized, being shock, and the like.

The methods of the present disclosure provide for analysis of abiological sample from a subject or a set of subjects. The subject(s)may be, e.g., any animal (e.g., a mammal), including but not limited tohumans, non-human primates, rodents, dogs, cats, pigs, fish, and thelike. The present methods and compositions can apply to biologicalsamples from humans, as described herein.

A biological sample can be obtained by methods known in the art such asthe biopsy methods provided herein, swabbing, scraping, phlebotomy, orany other suitable method. The biological sample can be obtained,stored, or transported using components of a kit of the presentdisclosure. In some cases, multiple biological samples, such as multiplethyroid samples, can be obtained for analysis, characterization, ordiagnosis according to the methods of the present disclosure. In somecases, multiple biological samples, such as one or more samples from onetissue type (e.g., thyroid) and one or more samples from another tissuetype (e.g., buccal) can be obtained for diagnosis or characterization bythe methods of the present disclosure. In some cases, multiple samples,such as one or more samples from one tissue type (e.g., thyroid) and oneor more samples from another tissue (e.g., buccal) can be obtained atthe same or different times. In some cases, the samples obtained atdifferent times are stored and/or analyzed by different methods. Forexample, a sample can be obtained and analyzed by cytological analysis(e.g., using routine staining). In some cases, a further sample can beobtained from a subject based on the results of a cytological analysis.The diagnosis of cancer or other condition can include an examination ofa subject by a physician, nurse or other medical professional. Theexamination can be part of a routine examination, or the examination canbe due to a specific complaint including, but not limited to, one of thefollowing: pain, illness, anticipation of illness, presence of asuspicious lump or mass, a disease, or a condition. The subject may ormay not be aware of the disease or condition. The medical professionalcan obtain a biological sample for testing. In some cases the medicalprofessional can refer the subject to a testing center or laboratory forsubmission of the biological sample. The methods of obtaining providedherein include methods of biopsy including fine needle aspiration, coreneedle biopsy, vacuum assisted biopsy, incisional biopsy, excisionalbiopsy, punch biopsy, shave biopsy or skin biopsy. In some cases, themethods and compositions provided herein are applied to data only frombiological samples obtained by FNA. In some cases, the methods andcompositions provided herein are applied to data only from biologicalsamples obtained by FNA or surgical biopsy. In some cases, the methodsand compositions provided herein are applied to data only frombiological samples obtained by surgical biopsy. A biological sample canbe obtained by non-invasive methods, such methods including, but notlimited to: scraping of the skin or cervix, swabbing of the cheek,saliva collection, urine collection, feces collection, collection ofmenses, tears, or semen. The biological sample can be obtained by aninvasive procedure, such procedures including, but not limited to:biopsy, alveolar or pulmonary lavage, needle aspiration, or phlebotomy.The method of biopsy can further include incisional biopsy, excisionalbiopsy, punch biopsy, shave biopsy, or skin biopsy. The method of needleaspiration can further include fine needle aspiration, core needlebiopsy, vacuum assisted biopsy, or large core biopsy. Multiplebiological samples can be obtained by the methods herein to ensure asufficient amount of biological material. Methods of obtaining suitablesamples of thyroid are known in the art and are further described in theATA Guidelines for thyroid nodule management (Cooper et al. Thyroid Vol.16 No. 2 2006), herein incorporated by reference in its entirety.Generic methods for obtaining biological samples are also known in theart and further described in for example Ramzy, Ibrahim ClinicalCytopathology and Aspiration Biopsy 2001 which is herein incorporated byreference in its entirety. The biological sample can be a fine needleaspirate of a thyroid nodule or a suspected thyroid tumor. The fineneedle aspirate sampling procedure can be guided by the use of anultrasound, X-ray, or other imaging device.

In some cases, the subject can be referred to a specialist such as anoncologist, surgeon, or endocrinologist for further diagnosis. Thespecialist can likewise obtain a biological sample for testing or referthe individual to a testing center or laboratory for submission of thebiological sample. In any case, the biological sample can be obtained bya physician, nurse, or other medical professional such as a medicaltechnician, endocrinologist, cytologist, phlebotomist, radiologist, or apulmonologist. The medical professional can indicate the appropriatetest or assay to perform on the sample, or the molecular profilingbusiness of the present disclosure can consult on which assays or testsare most appropriately indicated. The molecular profiling business canbill the individual or medical or insurance provider thereof forconsulting work, for sample acquisition and or storage, for materials,or for all products and services rendered.

A medical professional need not be involved in the initial diagnosis orsample acquisition. An individual can alternatively obtain a samplethrough the use of an over the counter kit. The kit can contain a meansfor obtaining said sample as described herein, a means for storing thesample for inspection, and instructions for proper use of the kit. Insome cases, molecular profiling services are included in the price forpurchase of the kit. In other cases, the molecular profiling servicesare billed separately.

A biological sample suitable for use by the molecular profiling businesscan be any material containing tissues, cells, nucleic acids, genes,gene fragments, expression products, gene expression products, and/orgene expression product fragments of an individual to be tested. Methodsfor determining sample suitability and/or adequacy are provided. Thebiological sample can include, but is not limited to, tissue, cells,and/or biological material from cells or derived from cells of anindividual. The sample can be a heterogeneous or homogeneous populationof cells or tissues. The biological sample can be obtained using anymethod known to the art that can provide a sample suitable for theanalytical methods described herein.

Obtaining a biological sample can be aided by the use of a kit. A kitcan be provided containing materials for obtaining, storing, and/orshipping biological samples. The kit can contain, for example, materialsand/or instruments for the collection of the biological sample (e.g.,sterile swabs, sterile cotton, disinfectant, needles, syringes,scalpels, anesthetic swabs, knives, curette blade, liquid nitrogen,etc.). The kit can contain, for example, materials and/or instrumentsfor the storage and/or preservation of biological samples (e.g.,containers; materials for temperature control such as ice, ice packs,cold packs, dry ice, liquid nitrogen; chemical preservatives or bufferssuch as formaldehyde, formalin, paraformaldehyde, glutaraldehyde,alcohols such as ethanol or methanol, acetone, acetic acid, HOPEfixative (Hepes-glutamic acid buffer-mediated organic solvent protectioneffect), heparin, saline, phosphate buffered saline, TAPS, bicine, Tris,tricine, TAPSO, HEPES, TES, MOPS, PIPES, cadodylate, SSC, MES, phosphatebuffer; protease inhibitors such as aprotinin, bestatin, calpaininhibitor I and II, chymostatin, E-64, leupeptin, alpha-2-macroglobulin,pefabloc SC, pepstatin, phenylmethanesufonyl fluoride, trypsininhibitors; DNAse inhibitors such as 2-mercaptoethanol,2-nitro-5-thicyanobenzoic acid, calcium, EGTA, EDTA, sodium dodecylsulfate, iodoacetate, etc.; RNAse inhibitors such as ribonucleaseinhibitor protein; double-distilled water; DEPC (diethyprocarbonate)treated water, etc.). The kit can contain instructions for use. The kitcan be provided as, or contain, a suitable container for shipping. Theshipping container can be an insulated container. The shipping containercan be self -addressed to a collection agent (e.g., laboratory, medicalcenter, genetic testing company, etc.). The kit can be provided to asubject for home use or use by a medical professional. Alternatively,the kit can be provided directly to a medical professional.

One or more biological samples can be obtained from a given subject. Insome cases, between about 1 and about 50 biological samples are obtainedfrom the given subject; for example, about 1-50, 1-40, 1-30, 1-25, 1-20,1-15, 1-10, 1-7, 1-5, 5-50, 5-40, 5-30, 5-25, 5-15, 5-10, 10-50, 10-40,10-25, 10-20, 25-50, 25-40, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, or 50 biological samples can be obtained from the givensubject. Multiple biological samples from the given subject can beobtained from the same source (e.g., the same tissue), e.g., multipleblood samples, or multiple tissue samples, or from multiple sources(e.g., multiple tissues). Multiple biological samples from the givensubject can be obtained at the same time or at different times. Multiplebiological samples from the given subject can be obtained at the samecondition or different condition. Multiple biological samples from thegiven subject can be obtained at the same disease progression ordifferent disease progression of the subject. If multiple biologicalsamples are collected from the same source (e.g., the same tissue) fromthe particular subject, the samples can be combined into a singlesample. Combining samples in this way can ensure that enough material isobtained for testing and/or analysis.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein. The starting materialsand reagents used for the synthesis of the compounds described hereinmay be synthesized or can be obtained from commercial sources, such as,but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and FischerScientific.

A: Biological Examples Example A1 Splicing Assay (MAPTau, MADD, FOXM1)

Various cells lines are treated with SMSMs described herein. RNA is thenisolated, cDNA synthesized, qPCR performed and the levels of variousmRNA targets of the SMSMs are determined. In some instances, RNA isisolated, cDNA synthesized, qPCR performed and the levels of mRNAisoforms in the various cell samples is determined.

Materials

Cells to Ct kit: ThermoFisher, AM1728. TaqMan Gene Expression MasterMix: ThermoFisher, 4369542. PPIA probe/primer: ThermoFisher,Hs03045993_gH, VIC-MGB_PL.

Probe/primer sequences: FoxM1 FOXM1 A2 probe/primer: IDT DNA Primer 1:(SEQ ID NO: 77) ACA GGT GGT GTT TGG TTA CA Primer 2: (SEQ ID NO: 78)AAA TTA AAC AAG CTG GTG ATG GG Probe: (SEQ ID NO: 79)/56-FAM/AG TTC TTT A/Zen/G TGG CGA TCT GCG AGA /3IABkFQ/FOXM1 BC probe/primer: IDT DNA Primer 1: (SEQ ID NO: 80)GAG CTT GCC CGC CAT AG Primer 2: (SEQ ID NO: 81)CTG GTC CTG CAG AAG AAA GAG Probe: (SEQ ID NO: 82)/5HEX/CC AAG GTG C/ZEN/T GCT AGC TGA GGA /3IABkFQ/ MADD Isoform 4 (WT)Primer 1: (SEQ ID NO: 83) GGC TAA ATA CTC TAA TGG AGA TTG TTA CPrimer 2: (SEQ ID NO: 84) GGC TGT GTT TAA TGA CAG ATG AC Probe:(SEQ ID NO: 85) /5HEX/AG TGG TGA A/ZEN/G GAA ACA GGA GGG CGT TAG/3IABkFQ/ Isoform 3 (Ex16) Primer 1: (SEQ ID NO: 86)CAC TGT TGG GCT GTG TTT AAT G Primer 2: (SEQ ID NO: 87)ACA GTA CCA GCT TCA GTC TTT C Probe: (SEQ ID NO: 88)/56-FAM/TC TGA AAG G/ZEN/A AAC AGG AGG GCG TT /3IABkFQ/ MAPTauMAPT Full length (4R) probe/primer: IDT DNA Primer 1: (SEQ ID NO: 89)CCA TGC CAG ACC TGA AGA AT Primer 2: (SEQ ID NO: 90)TTG GAC TGG ACG TTG CTA AG Probe: (SEQ ID NO: 91)/5HEX/AA TTA TCT G/ZEN/C ACC TTC CCG CCT CC/ 3IABkFQ/MAPT Truncation (3R) probe/primer: IDT DNA Primer 1: (SEQ ID NO: 92)AGA TCG GCT CCA CTG AGA A Primer 2: (SEQ ID NO: 93)GGT TTA TGA TGG ATG TTG CCT AAT G Probe: (SEQ ID NO: 94)/56-FAM/CA ACT GGT T/ZEN/T GTA GAC TAT TTG CAC CTT CCC /3IABkFQ/

Cells:

Cells used include 93T449, A-375, A-673, ASPC-1, BxPC-3, CCL-136, Daoy,DU-145, G-401, Hep-3B, IMR-32, K-562, LP-LoVo, MDA-MB-157,MDA-MB-231-luc, MDA-MB-468, MG-63, Ms751, NCI-H358, PACA-2, PANC-1,PC-3, RGX-MPC-11, RGX-PACA-2, SH-SY5Y, SJSA, SKOV3, SNU-16, SW872(HTB-92), TOLEDO, T.T, U-118, U-251MG, U-87MG, and Z-138 cells.

On the day of the experiment, a 96-well plate is seeded with the celllines of interest. The cells are diluted with full growth media to aconcentration of 2.0×10⁵ cells/mL and 100 μL of cells are added to eachwell (20,000 cells per well). The cells are treated with a compoundimmediately after plating.

The compounds are then added to the cell plate using the HP compounddispenser. In the initial experiment, a top concentration of 10 μM andan 8 point 4-fold dilution scheme is used. The stock compounds are madeat a concentration of 5 mM, and the DMSO concentration is set to 0.2%.DMSO is used to normalize all the compound-containing wells and theuntreated cells.

The treated cells are incubated at 37° C. in a 5% CO₂ incubator for thedesired amount of time. Plates are placed in a plastic bag with a wetpaper towel to prevent evaporation.

RNA is isolated using the Cells to C_(T) kit (ThermoFisher, AM1728). Thecells are washed once with 100 μL cold PBS. 50 μL of lysis buffer isadded to each well/tube (49.5 μL lysis buffer+0.5 μL DNase I perwell/tube). The lysis reaction is mixed and incubated at roomtemperature for 5 minutes. 5 μL of stop solution is added directly intoeach cell lysis reaction and mixed by pipetting up and down 5 times. Theplates/tubes are incubated at room temperature for 2 minutes then placedon ice if the cDNA synthesis is to be performed immediately. Otherwise,the plates/tubes are stored at −80° C. cDNA synthesis reactions are thenperformed. Reverse Transcription (RT) Master mix is prepared accordingto the table below.

Component Each reaction 2x RT Buffer 25 μL 20x RT Enzyme Mix 2.5 μLNuclease-free water 12.5 μL

40 μL RT master mix is added to PCR tubes or plate wells. 10 μL of RNAis added to each tube/well. The RT thermal cycler program is then runand tubes or plate wells are incubated at 37° C. for 1 hour, then at 95°C. for 5 minutes to deactivate the enzyme.

The qPCR is performed using a QuantStudio 6 instrument (ThermoFisher)and the following cycling conditions and according to the tables below.All samples and standards are analyzed in triplicate. Cycle 1: 2 minutesat 50° C. Cycle 2: 10 minutes at 95° C. Cycle 3 (repeat 40 times): 15seconds at 95° C., 1 minute at 60° C.

Isoform 1 or Isoform 2 Standard Samples

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xisoform 1 or isoform 2 probe/primer 0.5 μL Nuclease-free water 4.5 μLStandard DNA 5 μLUnknown Sample (FOXM1 isoform A2/FOXM1 Isoform BC Quantitation)

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xisoform 1 probe/primer 0.5 μL 40x isoform 2 probe/primer 0.5 μLNuclease-free water 5 μL Sample DNA 4 μL

PPIA Standard Sample

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 4.67 μL Standard DNA 5 μL

Unknown Sample (PPIA Quantitation)

Component Per qPCR well 2x TaqMan Gene Expression Master 10 μL Mix 60xPPIA probe/primer 0.33 μL Nuclease-free water 5.67 μL Sample DNA 4 μL

The determined isoform 2 and isoform 1 quantities are then be used todetermine the isoform 2:isoform 2 ratio at the various compoundconcentrations. The PPIA quantities are used in the normalization toaccount of cell proliferation effects of the compounds.

Standard Construction

PPIA standard (5834 bps) G Block sequence (IDT DNA) (SEQ ID NO: 95)GAATTCGGCCAGGCTCGTGCCGTTTTGCAGACGCCACCGCCGAGGAAAACCGTGTACTATTAGCCATGGTCAACCCCACCGTGTTCTTCGACATTGCCGTCGACGGCGAGCCCTTGGGCCGCGTCTCCTTTGAGCTGTTTGCAGACAAGGTCCCAAAGACAGCAGAAAATTTTCGTGCTCTGAGCACTGGAGAGAAAGGATTTGGTTATAAGGGTTCCTGCTTTCACAGAATTATTCCAGGGTTTATGTGTCAGGGTGGTGACTTCACACGCCATAATGGCACTGGTGGCAAGTCCATCTATGGGGAGAAATTTGAAGATGAGAACTTCATCCTAAAGCATACGGGTCCTGGCATCTTGTCCATGGCAAATGCTGGACCCAACACAAATGGTTCCCGCGGCCGC. FoxM1 A2 (5558 bps)G Block sequence (IDT DNA) (SEQ ID NO: 96)GAATTCGTTTTTGGGGAACAGGTGGTGTTTGGTTACATGAGTAAGTTCTTTAGTGGCGATCTGCGAGATTTTGGTACACCCATCACCAGCTTGTTTAATTTTATCTTTCTTTGTTTATCAGCGGCCGC FoxM2 BC (6439 bps)G Block sequence (IDT DNA) (SEQ ID NO: 97)GAATTCGGCGGAAGATGAAGCCACTGCTACCACGGGTCAGCTCATACCTGGTACCTATCCAGTTCCCGGTGAACCAGTCACTGGTGTTGCAGCCCTCGGTGAAGGTGCCATTGCCCCTGGCGGCTTCCCTCATGAGCTCAGAGCTTGCCCGCCATAGCAAGCGAGTCCGCATTGCCCCCAAGGTGCTGCTAGCTGAGGAGGGGATAGCTCCTCTTTCTTCTGCAGGACCAGGGAAAGAGGAGAAACTCCTGTTTGGAGAAGGGTTTTCTCCTTTGCTTCCAGTTCAGACTATCAAGGAGGAAGAAATCCAGCCTGGGGAGGAAATGCCACACTTAGCGAGACCCATCAAAGTGGAGAGCCCTCCCTTGGAAGAGTGGCCCTCCCCGGCCCCATCTTTCAAAGAGGAATCATCTCACTCCTGGGAGGATTCGTCCCAATCTCCCACCCCAAGACCCAAGAAGTCCTACAGTGGGCTTAGGTCCCCAACCCGGTGTGTCTCGGAAATGCTTGTGATTCAACACAGGGAGAGGAGGGAGAGGAGCCGGTCTCGGAGGAAACAGCATCTACTGCCTCCCTGTGTGGATGAGCCGGAGCTGCTCTTCTCAGAGGGGCCCAGTACTTCCCGCTGGGCCGCAGAGCTCCCGTTCCCAGCAGACTCCTCTGACCCTGCCTCCCAGCTCAGCTACTCCCAGGAAGTGGGAGGACCTTTTAAGACACCCATTAAGGAAACGCTGCCCATCTCCTCCACCCCGAGCAAATCTGTCCTCCCCAGAACCCCTGAATCCTGGAGGCTCACGCCCCCAGCCAAAGTAGGGGGACTGGATTTCAGCCCAGTACAAACCTCCCAGGGTGCCTCTGACCCCTTGCCTGACCCCCTGGGGCTGATGGATCTCAGCACCACTCCCTTGCAAAGTGCTCCCCCCCTTGAATCACCGCAAAGGCTCCTCAGTTCAGAACCCTTAGACCTCATCTCCGTCCCCTTTGGCAACTCTTCTCCCTCAGCGGCCGC MADD Isoform 4 (WT) (5668 bps)G Block sequence (IDT DNA) (SEQ ID NO: 98)GAATTCAAAGGTGCCCGAGAGAAGGCCACGCCCTTCCCCAGTCTGAAAGTATTTGGGCTAAATACTCTAATGGAGATTGTTACTGAAGCCGGCCCCGGGAGTGGTGAAGGAAACAGGAGGGCGTTAGTGGATCAGAAGTCATCTGTCATTAAACACAGCCCAACAGTGAAAAGAGAACCTCCATCACCCCAGGGTCGATCCAGCAATTCTAGTGAGAACCAGCAGTTCCTGCGGCCGC MADD Isoform 3 (Ex16) (5689 bps)G Block sequence (IDT DNA) (SEQ ID NO: 99)GAATTCACCGAGGGCTTCGGGGGCATCATGTCTTTTGCCAGCAGCCTCTATCGGAACCACAGTACCAGCTTCAGTCTTTCAAACCTCACACTGCCCACCAAAGGTGCCCGAGAGAAGGCCACGCCCTTCCCCAGTCTGAAAGGAAACAGGAGGGCGTTAGTGGATCAGAAGTCATCTGTCATTAAACACAGCCCAACAGTGAAAAGAGAACCTCCATCACCCCAGGGTCGATCCAGCAATTCTAGTGAGAAGCGG CCGCMAPTau Full length (4R) (5654 bps) G Block sequence (IDT DNA)(SEQ ID NO: 100) GAATTCTCCGCCAAGAGCCGCCTGCAGACAGCCCCCGTGCCCATGCCAGACCTGAAGAATGTCAAGTCCAAGATCGGCTCCACTGAGAACCTGAAGCACCAGCCGGGAGGCGGGAAGGTGCAGATAATTAATAAGAAGCTGGATCTTAGCAACGTCCAGTCCAAGTGTGGCTCAAAGGATAATATCAAACACGTCCCGGGAGGC GGCAGTGTGCAAGCGGCCGCMAPTau Truncation (3R) (5644 bps) G Block sequence (IDT DNA)(SEQ ID NO: 101) GAATTCTCAAGTCCAAGATCGGCTCCACTGAGAACCTGAAGCACCAGCCGGGAGGCGGGAAGGTGCAAATAGTCTACAAACCAGTTGACCTGAGCAAGGTGACCTCCAAGTGTGGCTCATTAGGCAACATCCATCATAAACCAGGAGGTGGCCAGGTGGAAGTAAAATCTGAGAAGCTTGACTTCAAGGACAGAGTCCAGTCGA AGGCGGCCGC

The G Blocks are inserted into the pCI-neo mammalian expression vector(Promega) at the EcoRI and NotI restriction sites (bolded) usingInfusion cloning technology (Clontech). The plasmids are then purifiedusing standard miniprep or maxiprep kits (Macherey Nagel).

Standard Curve Preparation

The dilution necessary to make the top standard is calculated. A topconcentration 200,000,000 copies/μL of the stock plasmid is prepared inTE buffer. A series of 10-fold dilutions, also in TE, are then made. Atotal of 5 μL of each standard is used in a qPCR well to generatesamples containing 10⁹ copies, 10⁸ copies, 10⁷ copies, 10⁶ copies, 10⁵copies, 10⁴ copies, 10³ copies, 10² copies, 10¹ copies, and 0 copies.

An assay to measure the FOXM1^(A2) mRNA and FOXM1^(BC) mRNA, orMADD^(WT (isoform 4)) mRNA and mADD^(Ex16 (isoform 3)) mRNA, orMAPTau^(4R) mRNA and MAPTau^(3R) mRNA simultaneously in cell wells isperformed. The RNA values are measured relative to DMSO control and alsoincluded a housekeeping gene, PPIA to ensure data is consistent. ThemRNA values are measured after 24 hours of incubation with the SMSMcompounds. The SMSMs dose dependently increased FOXM1^(A2) levels whileconcomitantly decreasing FOXM1^(BC) levels with EC₅₀ and IC₅₀ values inthe nanomolar range.

Example A2 SMN2 Splicing Assay—Monitoring Expression Levels of SMN2Splice Variant Using Real-Time Quantitative PCR

Various cells lines are treated with the SMSMs described herein. RNA isthen isolated, cDNA synthesized, qPCR performed and the levels ofvarious mRNA targets of the SMSMs are determined. In some instances, RNAis isolated, cDNA synthesized, qPCR performed and the levels of mRNAisoforms in the various cell samples are determined.

Materials

Cells to Ct kit: ThermoFisher, AM1728. TaqMan Gene Expression MasterMix: ThermoFisher, 4369542. PPIA probe/primer: ThermoFisher,Hs03045993_gH, VIC-MGB_PL.

Probe/Primer Sequences:

The table below summarizes primers that can be used.

Sequence (5′-3′) Primer Primer 5′-Mod. 3′-Mod. SpeciesGCT CAC ATT CCT TAA FL Forward 0.04 μmol None None HumanATT AAG GAG AAA (SEQ Primer ID NO: 102) TGG CTA TCA TAC TGG Δ7 Forward0.04 μmol None None Human CTA TTA TAT GGA A (SEQ Primer ID NO: 103)TCC AGA TCT GTC TGA Reverse Primer 0.04 μmol None None HumanTCG TTT CTT (SEQ ID NO: 104) CTG GCA TAG AGC AGC Probe  0.2 μmol FAMBHQ-1 Human ACT AAA TGA CAC CAC (Fluorescein) (SEQ ID NO: 105)

Cells:

SMA type I patient cells (GM03813 (Coriell))

Protocol

On the day of the experiment, a 96-well plate is seeded with the celllines of interest. The cells are diluted with full growth media to aconcentration of 2.0×10⁵ cells/mL and 100 μL of cells are added to eachwell (20,000 cells per well). The cells are treated with a compoundimmediately after plating.

The compounds are then added to the cell plate using the HP compounddispenser. In the initial experiment, a top concentration of 10 μM andan 8 point 4-fold dilution scheme is used. The stock compounds are madeat a concentration of 5 mM, and the DMSO concentration is set to 0.2%.DMSO is used to normalize all the compound-containing wells and theuntreated cells.

The treated cells are incubated at 37° C. in a 5% CO₂ incubator for thedesired amount of time. Plates are placed in a plastic bag with a wetpaper towel to prevent evaporation.

RNA is isolated using the Cells to C_(T) kit (ThermoFisher, AM1728). Thecells are washed once with 100 μL cold PBS. 50 μL of lysis buffer isadded to each well/tube (49.5 μL lysis buffer+0.5 μL DNase I perwell/tube). The lysis reaction is mixed and incubated at roomtemperature for 5 minutes. 5 μL of stop solution is added directly intoeach cell lysis reaction and mixed by pipetting up and down 5 times. Theplates/tubes are incubated at room temperature for 2 minutes then placedon ice if the cDNA synthesis is to be performed immediately. Otherwise,the plates/tubes are stored at −80° C.

cDNA synthesis reactions are then performed. 40 μL RT master mix isadded to PCR tubes or plate wells. 10 μL of RNA is added to eachtube/well. The RT thermal cycler program is then run and tubes or platewells are incubated at 37° C. for 1 hour, then at 95° C. for 5 minutesto deactivate the enzyme.

The qPCR is performed using a QuantStudio 6 instrument (ThermoFisher)and the following cycling conditions and according to the tables below.All samples and standards are analyzed in triplicate. Cycle 1: 2 minutesat 50° C. Cycle 2: 10 minutes at 95° C. Cycle 3 (repeat 40 times): 15seconds at 95° C., 1 minute at 60° C.

SMN2^(FL) or SMN2^(Δ7) Standard Samples

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xSMN2^(FL) or SMN2^(Δ7) probe/primer 0.5 μL Nuclease-free water 4.5 μLStandard DNA 5 μL

Unknown Sample (FOXM1 Isoform A2/FOXM1 Isoform BC Quantitation)

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xSMN2^(FL) probe/primer 0.5 μL 40x SMN2^(Δ7) probe/primer 0.5 μLNuclease-free water 5 μL Sample DNA 4 μL

PPIA Standard Sample

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 4.67 μL Standard DNA 5 μL

Unknown Sample (PPIA Quantitation)

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 5.67 μL Sample DNA 4 μL

The determined SMN2^(Δ7) and SMN2^(FL) quantities are then be used todetermine the SMN2^(Δ7):SMN2^(FL) ratio at the various compoundconcentrations. The PPIA quantities are used in the normalization toaccount of cell proliferation effects of the compounds.

Standard Construction

PPIA standard (5834 bps) G Block sequence (IDT DNA) (SEQ ID NO: 95)GAATTCGGCCAGGCTCGTGCCGTTTTGCAGACGCCACCGCCGAGGAAAACCGTGTACTATTAGCCATGGTCAACCCCACCGTGTTCTTCGACATTGCCGTCGACGGCGAGCCCTTGGGCCGCGTCTCCTTTGAGCTGTTTGCAGACAAGGTCCCAAAGACAGCAGAAAATTTTCGTGCTCTGAGCACTGGAGAGAAAGGATTTGGTTATAAGGGTTCCTGCTTTCACAGAATTATTCCAGGGTTTATGTGTCAGGGTGGTGACTTCACACGCCATAATGGCACTGGTGGCAAGTCCATCTATGGGGAGAAATTTGAAGATGAGAACTTCATCCTAAAGCATACGGGTCCTGGCATCTTGTCCATGGCAAATGCTGGACCCAACACAAATGGTTCCCGCGGCCGC

-   SMN2^(FL) standard G Block sequence (IDT DNA) are used-   SMN2^(Δ7) standard G Block sequence (IDT DNA) are used

The G Blocks are inserted into the pCI-neo mammalian expression vector(Promega) at the EcoRI and NotI restriction sites (bolded) usingInfusion cloning technology (Clontech). The plasmids are then purifiedusing standard miniprep or maxiprep kits (Macherey Nagel).

Standard Curve Preparation

The dilution to make the top standard is calculated. A top concentration200,000,000 copies/μL of the stock plasmid is prepared in TE buffer. Aseries of 10-fold dilutions, also in TE, are then made. A total of 5 μLof each standard is used in a qPCR well to generate samples containing10⁹ copies, 10⁸ copies, 10⁷ copies, 10⁶ copies, 10⁵ copies, 10⁴ copies,10³ copies, 10² copies, 10¹ copies, and 0 copies.

An assay to measure the SMN2^(FL) mRNA and SMN2^(Δ7) mRNA simultaneouslyin cell wells is performed. The RNA values are measured relative to DMSOcontrol and also included a housekeeping gene, PPIA to ensure data isconsistent. The mRNA values are measured after 24 hours of incubationwith the SMSM compounds. The SMSMs dose dependently increased theSMN2^(FL) values while concomitantly decreasing the SMN2^(Δ7) values atthe same with EC₅₀ and IC₅₀ values in the nanomolar range.

Additionally, to monitor expression levels of SMN2 splice variant usingreal-time quantitative PCR, SMA type I patient cells (GM03813 (Coriell))are plated at 5,000 cells/well in 200 μl Dulbecco's modified Eagle'smedium (DMEM) with GlutaMAX and 10% fetal bovine serum (FBS) (LifeTechnologies, Inc.) in 96-well plates, and incubated for 6 hours in acell culture incubator. Cells are then treated with SMSMs at differentconcentrations (0.5% DMSO) in duplicate for 24 hours. After removal ofthe supernatant, cells are lysed in Cells-To-Ct lysis buffer (LifeTechnologies, Inc.) according to the manufacturer's recommendations. ThemRNA levels of SMN2 FL, SMN2 Δ7 are quantified using Taqman-basedRT-qPCR and SMN2-specific primers and probes. The SMN2 forward andreverse primers are each used at a final concentration of 0.4 μM. TheSMN2 probe is used at a final concentration of 0.15 μM. RT-qPCR iscarried out at the following temperatures for indicated times: Step 1:48° C. (15 min); Step 2: 95° C. (10 min); Step 3: 95° C. (15 sec); Step4: 60° C. (1 min); Steps 3 and 4 are repeated for 40 cycles. The Ctvalues for each mRNA are converted to mRNA abundance using actual PCRefficiencies.

Example A3 IKBKAP Splicing Assay

Various cells lines are treated with the SMSMs described herein. RNA isthen isolated, cDNA synthesized, qPCR performed and the levels of IKBKAPtargets of the SMSMs are determined.

Materials

Cells to Ct kit: ThermoFisher, AM1728. TaqMan Gene Expression MasterMix: ThermoFisher, 4369542. PPIA probe/primer: ThermoFisher,Hs03045993_gH, VIC-MGB_PL.

Probe/primer sequences: IKBKAP IKBKAP WT probe/primer: IDT DNA Primer 1:(SEQ ID NO: 106) ACC AGG GCT CGA TGA TGA A Primer 2: (SEQ ID NO: 107)GCA GCA ATC ATG TGT CCC A Probe: (SEQ ID NO: 108)/56-FAM/GT TCA CGG A/ZEN/T TGT CAC TGT TGT GCC /3IABkFQ/IKBKAP MU probe/primer: IDT DNA Primer 1: (SEQ ID NO: 109)GAA GGT TTC CAC ATT TCC AAG Primer 2: (SEQ ID NO: 110)CAC AAA GCT TGT ATT ACA GAC T Probe: (SEQ ID NO: 111)/5HEX/CT CAA TCT G/ZEN/A TTT ATG ATC ATA ACC CTA AGG TG/3IABkFQ/

Protocol

On the day of the experiment, a 96-well plate is seeded with the celllines of interest. The cells are diluted with full growth media to aconcentration of 2.0×10⁵ cells/mL and 100 μL of cells are added to eachwell (20,000 cells per well). The cells are treated with a compoundimmediately after plating.

The compounds are then added to the cell plate using the HP compounddispenser. In the initial experiment, a top concentration of 10 μM andan 8 point 4-fold dilution scheme is used. The stock compounds are madeat a concentration of 5 mM, and the DMSO concentration is set to 0.2%.DMSO is used to normalize all the compound-containing wells and theuntreated cells.

The treated cells are incubated at 37° C. in a 5% CO₂ incubator for thedesired amount of time. Plates are placed in a plastic bag with a wetpaper towel to prevent evaporation.

RNA is isolated using the Cells to CT kit (ThermoFisher, AM1728). Thecells are washed once with 100 μL cold PBS. 50 μL of lysis buffer isadded to each well/tube (49.5 μL lysis buffer+0.5 μL DNase I perwell/tube). The lysis reaction is mixed and incubated at roomtemperature for 5 minutes. 5 μL of stop solution is added directly intoeach cell lysis reaction and mixed by pipetting up and down 5 times. Theplates/tubes are incubated at room temperature for 2 minutes then placedon ice if the cDNA synthesis is to be performed immediately. Otherwise,the plates/tubes are stored at −80° C.

cDNA synthesis reactions are then performed. 40 μL RT master mix isadded to PCR tubes or plate wells. 10 μL of RNA is added to eachtube/well. The RT thermal cycler program is then run and tubes or platewells are incubated at 37° C. for 1 hour, then at 95° C. for 5 minutesto deactivate the enzyme.

The qPCR is performed using a QuantStudio 6 instrument (ThermoFisher)and the following cycling conditions and according to the tables below.All samples and standards are analyzed in triplicate. Cycle 1: 2 minutesat 50° C. Cycle 2: 10 minutes at 95° C. Cycle 3 (repeat 40 times): 15seconds at 95° C., 1 minute at 60° C.

IKBKAP^(FL) or IKBKAP^(Δ20) Standard Samples

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xIKBKAP^(FL) or IKBKAP^(Δ20) probe/primer 0.5 μL Nuclease-free water 4.5μL Standard DNA 5 μL

Unknown Sample (IKBKAP^(FL)/IKBKAP^(Δ20) Quantitation)

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xIKBKAP^(FL) probe/primer 0.5 μL 40x IKBKAP^(Δ20) probe/primer 0.5 μLNuclease-free water 5 μL Sample DNA 4 μL

PPIA Standard Sample

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 4.67 μL Standard DNA 5 μL

Unknown Sample (PPIA Quantitation)

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 5.67 μL Sample DNA 4 μL

The determined IKBKAP^(FL) and IKBKAP^(Δ20) isoform quantities are thenused to determine the IKBKAP^(FL):IKBKAP^(Δ20) ratio at increasing SMSMcompound concentrations. The PPIA quantities are used in thenormalization to account of cell proliferation effects of the compounds.

Standard Construction

PPIA standard (5834 bps) G Block sequence (IDT DNA (SEQ ID NO: 95)GAATTCGGCCAGGCTCGTGCCGTTTTGCAGACGCCACCGCCGAGGAAAACCGTGTACTATTAGCCATGGTCAACCCCACCGTGTTCTTCGACATTGCCGTCGACGGCGAGCCCTTGGGCCGCGTCTCCTTTGAGCTGTTTGCAGACAAGGTCCCAAAGACAGCAGAAAATTTTCGTGCTCTGAGCACTGGAGAGAAAGGATTTGGTTATAAGGGTTCCTGCTTTCACAGAATTATTCCAGGGTTTATGTGTCAGGGTGGTGACTTCACACGCCATAATGGCACTGGTGGCAAGTCCATCTATGGGGAGAAATTTGAAGATGAGAACTTCATCCTAAAGCATACGGGTCCTGGCATCTTGTCCATGGCAAATGCTGGACCCAACACAAATGGTTCCCGCGGCCGC IKBKAP WT (5639 bps)(SEQ ID NO: 112) GAATTCCTTCATTTAAAACATTACAGGCCGGCCTGAGCAGCAATCATGTGTCCCATGGGGAAGTTCTGCGGAAAGTGGAGAGGGGTTCACGGATTGTCACTGTTGTGCCCCAGGACACAAAGCTTGTATTACAGATGCCAAGGGGAAACTTAGAAGTTGTTCATCATCGAGCCCTGGTTTTAGCTCAGATTCGGAAGTGGTGCG GCCGCIKBKAP MU (5645 bps) (SEQ ID NO: 113)GAATTCCGGATTGTCACTGTTGTGCCCCAGGACACAAAGCTTGTATTACAGACTTATGTTTAAAGAGGCATTTGAATGCATGAGAAAGCTGAGAATCAATCTCAATCTGATTTATGATCATAACCCTAAGGTGTTTCTTGGAAATGTGGAAACCTTCATTAAACAGATAGATTCTGTGAATCATATTAACTTGTTTTTTACAGA ATTGCGGCCGC

The G Blocks are inserted into the pCI-neo mammalian expression vector(Promega) at the EcoRI and NotI restriction sites (bolded) usingInfusion cloning technology (Clontech). The plasmids are then purifiedusing standard miniprep or maxiprep kits (Macherey Nagel).

Standard Curve Preparation

The dilution necessary to make the top standard is calculated. A topconcentration 200,000,000 copies/μL of the stock plasmid is prepared inTE buffer. A series of 10-fold dilutions, also in TE, are then made. Atotal of 5 μL of each standard is used in a qPCR well to generatesamples containing 10⁹ copies, 10⁸ copies, 10⁷ copies, 10⁶ copies,10⁵copies, 10⁴ copies, 10³ copies, 10² copies, 10¹ copies, and 0 copies.

An assay to measure the IKBKAP^(FL) mRNA and IKBKAP^(Δ20) mRNAsimultaneously in cell wells is performed. The RNA values are measuredrelative to DMSO control and also included a housekeeping gene, PPIA toensure data is consistent. The mRNA values are measured after 24 hoursof incubation with the SMSM compounds.

Example A4 Cell Viability and Proliferation

Small molecule splicing modulators are tested in a dose-response assayusing different cancer cell lines. Cells are first plated in 96-wellplastic tissue culture plates (10,000 cells per well). The cells aretreated with 500 nM of SMSM or vehicle alone (DMSO) for 48 hours.Following treatment, the cells are washed with PBS, stained with acrystal violet staining solution, and allowed to dry for 48-72 hrs.After drying, sodium citrate buffer is added to each well and allowed toincubate for 5 min at room temperature. The absorbance is measured at450 nM using a microplate reader (Biorad; Hercules, Calif.). Therelative cell proliferation for each of the cancer cell lines isdetermined.

To measure cell viability, cells are plated in 96-well plastic tissueculture plates at a density of 5×10³ cells/well. Twenty-four hours afterplating, cells are treated with various SMSMs. After 72 hours, the cellculture media are removed and plates are stained with 100 mL/well of asolution containing 0.5% crystal violet and 25% methanol, rinsed withdeionized water, dried overnight, and resuspended in 100 mL citratebuffer (0.1 M sodium citrate in 50% ethanol) to assess platingefficiency. Intensity of crystal violet staining, assessed at 570 nm andquantified using a Vmax Kinetic Microplate Reader and Softmax software(Molecular Devices Corp., Menlo Park, Calif.), are directly proportionalto cell number. Data are normalized to vehicle-treated cells and arepresented as the mean±SE from representative experiments. SMSMs that areeffective are determined for various cells lines.

Small molecule splicing modulators are tested in a dose-response assayusing cancer cells and NHDF cells.

Cancer cells or NHDF cells are first plated in 96-well plastic tissueculture plates (10,000 cells per well). The cells are treated withvehicle alone (DMSO), or increasing concentrations of SMSM compounds for72 h. Following treatment, cell proliferation is determined using acrystal violet assay. The relative cell proliferation at eachconcentration is determined.

Example A5 Monitoring Expression Levels of FOXM1 Splice Variants UsingReal-Time Quantitative PCR

Human fibroblasts are plated at 10,000 cells/well in 200 μL DMEM withGlutaMAX and 10% FBS in 96-well plates in a cell culture incubator (37°C., 5% CO₂, 100% relative humidity). Cells are then treated with SMSMsat different concentrations (0.1-1000 nM, each in 0.5% DMSO) intriplicate for 24 hours. RNA extraction is performed as per instructionsin the Cells-to-CT™ Kits (Ambion®, Applied Biosystems). RNA samples arefrozen at −20° C. until further analysis. Relative expression levels offull-length FOXM1 (FOXM1^(FL)) or FOXM1 lacking exon VIIa(FOXM1^(ΔVIIa)) with GAPDH for internal control, is measured usingone-step multiplex reverse transcription-polymerase chain reaction(RT-PCR). TaqMan® FAM probes are used for relative quantitation ofFOXM1^(FL) or FOXM1^(ΔVIIa) expression levels and TaqMan® VIC probes areused for relative quantitation of human GAPDH levels. The fidelity ofthe amplification methods is determined using the ΔΔCt relativequantification method for quantitative PCR.

Example A6 Maximum Tolerable Dose Study

Survival of mice after administration of SMSMs after 10 or 11 days isassessed.

Tolerance of the drug treatments is determined by measuring the weightof the mice during the period of drug administration. Body weight ismeasured prior to tumor inoculation and prior to the treatmentadministration and then daily. The changes in the final weight of themice for the SMSM treatments are determined.

Example A7 Dose Range and Time Course Studies

Dose range and time course studies comparing anti-neoplastic effects ofSMSMs against vehicle are conducted.

Exemplary experimental groups used for this study are shown in the tablebelow.

Group Dose Dosing Route of # Group Treatment (mg/kg) ScheduleAdministration Mice 1 Vehicle NA QDx14 PO 10 2 SMSM 3 mg/kg BIDx14 IP 103 SMSM 5 mg/kg BIDx14 PO 10 4 SMSM 7.5 mg/kg BIDx14 PO 10 5 SMSM 10mg/kg QDx14 PO 10

Female NCrNu mice are used. Age range of enrollment is 7-10 weeks. Atotal of 75 animals are for the studies.

Each mouse are inoculated into a right flank with the single cellsuspension of 95% viable tumor cells (5×10⁶ cells/mouse) in serum-freeRPMI 1640 Media for tumor development. Treatments are administered whenmean tumor size reached approximately 75 mm³.

An acclimation period of a minimum of 72 hrs is allowed between animalreceipt and tumor inoculation in order to accustom the animals to thelaboratory environment. Immunodeficient NCrNu mice are maintained in apathogen-free environment. Animals are fed a diet of Irradiated Mousepellet feed Purina rodent diet #5053 (Fisher Feeds, Bound Brook, N.J.)and chlorinated water from a reverse osmosis (RO) system (4-6 ppm).

Before commencement of treatment, all animals are weighed and assignedto treatment groups using a randomization procedure. Mice are randomizedinto groups based upon their tumor sizes to ensure that each group hadapproximately the same mean tumor size and range of tumor size.

After inoculation, the animals are checked daily for morbidity andmortality. At the time of routine monitoring, the animals are checkedfor any effects of tumor growth on normal behavior such as mobility,food and water consumption, body weight gain/loss, eye/hair matting andany other abnormal effects. Deaths and observed clinical signs arerecorded. Animals that are observed to be in a continuing deterioratingcondition or bearing a tumor exceeding 2,000 mm³ in size are euthanized.

Body weight is measured prior to tumor inoculation and prior to thetreatment administration and then daily. Tumor size are measured 2-3times per week in two dimensions using a caliper, and the volume areexpressed in mm³ using the formula: V=0.5×a×b² where a and b are thelong and short diameters of the tumor, respectively.

Studies are terminated when the tumor size in the vehicle treated groupreached 2,000 mm³. Each mouse is bled at 2 hrs after the last dose andat least 50 μl of plasma are collected from each mouse. All of thecollected plasma samples and retainer dosing solutions for each doselevel are used for bioanalytical measurements. All tumors are alsocollected and weighed. One necrosis-free tumor fragment of approximately50 mg is taken from each tumor and flash-frozen for RNA isolation. Theremaining tumor is flash frozen for PK analysis.

Example A8 In Vivo SMSM Treatment Effect on Inhibition of Tumor Growth

Studies are performed to assess the effects of in vivo SMSM treatment onvarious tumors. Studies are also performed to assess the effects of invivo SMSM treatment on mRNA levels. Immunocompromised nude mice withpre-existing cancer xenografts are treated with vehicle or SMSMs. Tumortissues from subcutaneous xenografts are broken into a powder using aBioPulverizer (Biospec Products, Inc.). After SMSM treatment, mRNA isisolated from the xenografts and is analyzed by qRT-PCR.

Tumor size is measured 2 times per week in two dimensions using acaliper. Studies are terminated when the tumor size in the vehicletreated group reached 2,000 mm³. Each mouse is bled at 2 hrs after thelast dose and at least 50 μl of plasma is collected from each mouse. Allof the collected plasma samples and retainer dosing solutions for eachdose level are used for bioanalytical measurements. All tumors are alsocollected and weighed. One necrosis-free tumor fragment of approximately50 mg is taken from each tumor and flash-frozen for RNA isolation. Theremaining tumor is flash frozen for PK analysis.

The effects of in vivo SMSM treatments on pre-existing subcutaneouscancer xenografts are assessed. For these in vivo experiments, 1×10⁶cancer cells (cells re-suspended in 100 μl PBS are subcutaneouslyinjected into the flanks of nude mice. When the tumor reachedapproximately 100 mm³ (volume=(3/4)(π)(length/2)(width/2)²), the SMSMtreatments are initiated.

Example A9 Quantitative Splicing Assay (SMN)

Spinal muscular atrophy (SMA) patient fibroblasts (GM03813, Coriell)were plated in 96-well plates at 50,000 cells/well. Immediately afterplating, cells were dosed with compounds for 24 h at concentrationsranging from 2.5 μM to 0.6 nM (0.1% DMSO). Treated cells were lysed andcDNA synthesized using the Fast Advanced Cells-to-Ct kit (ThermoFisherA35378) according to the manufacturer's instructions. 2 μL of each cDNAwere used in qPCR reactions. The qPCR reactions were prepared in384-well plates in 10 μL volume, using TaqMan™ Fast Advanced Master Mix(ThermoFisher; 4444965) with primers and probes shown in the tablebelow. Reactions were run in a Quant Studio 6 qPCR instrument withdefault settings.

Probe/primer sequences: SMN FL-FAM: Probe: (SEQ ID NO: 105)5′ CTGGCATAGAGCAGCACTAAATGACACCAC 3′ Primer 1: (SEQ ID NO: 102)5′ GCTCACATTCCTTAAATTAAGGAGAAA 3′ Primer 2: (SEQ ID NO: 104)5′ TCCAGATCTGTCTGATCGTTTCTT 3′ SMN Δ7-FAM: Probe: (SEQ ID NO: 105)5′ CTGGCATAGAGCAGCACTAAATGACACCAC 3′ Primer 1: (SEQ ID NO: 103)5′ TGGCTATCATACTGGCTATTATATGGAA 3′ Primer 2: (SEQ ID NO: 104)5′ TCCAGATCTGTCTGATCGTTTCTT 3′ TBP-YAK (endogenous control) Probe:(SEQ ID NO: 114) 5′ CCGCAGCTGCAAAATATTGTATCCACA 3′ Primer 1:(SEQ ID NO: 115) 5′ TCGGAGAGTTCTGGGATT 3′ Primer 2: (SEQ ID NO: 116)5′ AAGTGCAATGGTCTTTAGGT 3

TABLE 3 SMN Splicing Potency SMN Quantitative Splicing Assay Compound #FL EC₅₀ (nM) 1A — 1B — 2A — 2B A 3A A 3B A 4A — 4B — 5A — 5B — 0.01 nM ≤A ≤ 15 nM; 15 nM < B ≤ 50 nM; 50 nM < C ≤ 100 nM; 100 nM < D ≤ 500 nM;500 nM < E ≤ 10,000 nM

Example A10 SMN Protein Assay

Compounds were tested on spinal muscular atrophy (SMA) patientfibroblasts (GM03813, Coriell) at doses ranging from 2.5 μM to 0.6 nM.7000 cells/well were seeded in 96-well plates. Compounds were incubatedfor 48 hours and the cells were lysed with 100 μL of lysis buffer. 20 μLof lysate was used for SMN protein measurement by Mesoscale Discovery(MSD) assay developed by PharmOptima (Michigan). A standard curveprepared with SMN protein ranging from 1 μg/ml to 19.5 pg/ml was used ineach MSD plate to calculate the absolute SMN protein amount in eachsample.

One plate with 700 cells/well was prepared for parallel viabilitytesting by Cell Tier Glo reagents (Promega, G7572/G7573 (CTG). Theviability readout was carried out according to the manufacturer'sinstructions.

TABLE 4 SMN Protein Potency Compound # SMN EC₅₀ (nM) 1A E 1B E 2A E 2B A3A B 3B A 4A — 4B — 5A E 5B D 0.01 nM ≤ A ≤ 15 nM; 15 nM < B ≤ 50 nM; 50nM < C ≤ 100 nM; 100 nM < D ≤ 500 nM; 500 nM < E ≤ 10,000 nM

Example A11 Assessment of Blood-Brain-Barrier (BBB) PenetrationPotential via an MDCK-MDR1 Permeability Assay

The permeability of compounds was assessed for BBB penetration potentialby use of an MDCK-MDR1 assay (Catalog EA203) performed by AbsorptionSystems, Exton Pa. See, “Evaluation of the MDR-MDCK cell line as apermeability screen for the blood-brain barrier,” Wang, Q. Rager, J. D.;Weinstein, K.; Kardos, P. S.; Dobson, G. L.; Li, J.; Hidalgo, I. J.

Experimental Procedure:

MDR1-MDCK cell monolayers were grown to confluence on collagen-coated,microporous membranes in 12-well assay plates. The permeability assaybuffer was Hanks' balanced salt solution containing 10 mM HEPES and 15mM glucose at a pH of 7.4. The buffer in the receiver chamber alsocontained 1% bovine serum albumin. The dosing solution concentration was5 μM of test article in the assay buffer. Cell monolayers were dosed onthe apical side (A-to-B) or basolateral side (B-to-A) and incubated at37° C. with 5% CO₂ in a humidified incubator. Samples were taken fromthe donor and receiver chambers at 120 minutes. Each determination wasperformed in duplicate. The flux of lucifer yellow was also measuredpost-experimentally for each monolayer to ensure no damage was inflictedto the cell monolayers during the flux period. All samples were assayedby LC-MS/MS using electrospray ionization. Analytical conditions areoutlined below.

The apparent permeability (P_(app)) and percent recovery were calculatedas follows:

$\begin{matrix}{P_{app} = {\left( {{dC}_{r}\text{/}{dt}} \right) \times V_{r}\text{/}\left( {A \times C_{A}} \right)}} & (1) \\{{{Percent}\mspace{14mu}{Recovery}} = {100 \times \left( {\left( {V_{r} \times C_{r}^{final}} \right) + \left( {V_{d} \times C_{d}^{final}} \right)} \right)\text{/}\left( {V_{d} \times C_{N}} \right)}} & (2)\end{matrix}$

Where,

dC_(r)/dt is the slope of the cumulative concentration in the receivercompartment versus

time in μM s⁻¹;

V_(r) is the volume of the receiver compartment in cm³;

V_(d) is the volume of the donor compartment in cm³;

A is the area of the insert (1.13 cm² for 12-well);

C_(A) is the average of the nominal dosing concentration and themeasured 120 minute

donor concentration in μM;

C_(N) is the nominal concentration of the dosing solution in μM;

C_(r) ^(final) is the cumulative receiver concentration in μM at the endof the incubation period;

C_(d) ^(final) is the concentration of the donor in μM at the end of theincubation period.

Efflux ratio (ER) is defined as P_(app) (B-to-A)/P_(app) (A-to-B).

Analytical Method:

Liquid Chromatography

Column: Waters ACQUITY UPLC BEH Phenyl 30×2.1 mm, 1.7 μm

M.P. Buffer: 25 mM ammonium formate buffer, pH 3.5

Aqueous Reservoir (A): 90% water, 10% buffer

Organic Reservoir (B): 90% acetonitrile, 10% buffer

Flow Rate: 0.7 mL/minute

Gradient Program:

Time (min) % A % B 0.00 99 1 0.65 1 99 0.75 1 99 0.80 99 1 1.00 99 1

Total Run Time: 1.00 minute

Autosampler: 2 μL injection volume

Wash1: water/methanol/2-propanol:1/1/1; with 0.2% formic acid

Wash2: 0.1% formic acid in water

TABLE 5 MDCK-MDR1 Permeability Assay MDCK- MDCK- MDCK- MDCK- MDR1: %MDR1: % MDR1: MDR1: Recov Recov Papp A-B Papp B-A MDCK- Compound A-B B-A(10{circumflex over ( )}−6, (10{circumflex over ( )}−6, MDR1: # (%) (%)cm/s) cm/s) Efflux 1A 81 94 0.12 37.8 309 1B 95 84 0.3 46.4 152 2A 78 742.05 39.8 19 2B 93 96 2.26 53.4 24 3A 67 72 5.37 37.3 7 3B 62 76 4.337.8 9 4A 89 96 2.43 62.7 26 4B 91 101 3.05 50 16 5A 69 79 9 30.9 3 5B83 90 10.2 43.7 4

B: Chemical Examples

Experimental

Compounds described herein can be synthesized using standard synthetictechniques or using methods known in the art in combination with methodsdescribed herein. Unless otherwise indicated, conventional methods ofmass spectroscopy, NMR, HPLC, protein chemistry, biochemistry,recombinant DNA techniques and pharmacology can be employed. Compoundscan be prepared using standard organic chemistry techniques such asthose described in, for example, March's Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions forthe synthetic transformations described herein may be employed such asvariation of solvent, reaction temperature, reaction time, as well asdifferent chemical reagents and other reaction conditions. The startingmaterials can be available from commercial sources or can be readilyprepared. By way of example only, provided are schemes for preparing theExamples described herein.

The following abbreviations are used: DCM—dichloromethane;DIPEA—N,N-diisopropylethylamine; DMSO—dimethyl sulfoxide;DMF—N,N-dimethylformamide;EDCI—N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide; Et₂O—diethyl ether;EtOAc—ethyl acetate; EtOH—ethyl alcohol; HOBt—1-hydroxybenzotriazole;LCMS—liquid chromatography mass spectrometer; MeCN—acetonitrile;MeOH—methyl alcohol; Ms—mesylate; MTBE—methyl tert-butyl ether;Selectfluor—1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate); SFC—supercritical fluid chromatography;THF—tetrahydrofuran; TMSCl—trimethylsilyl chloride; h—hour; min—minute;rt—room temperature (22-25° C.); g—grams; mL—milliliters; mg—milligrams;mmol—millimoles.

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645X, in8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73volumes.

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. A detailed description oftechniques applicable to the creation of protecting groups and theirremoval are described in Greene and Wuts, Protective Groups in OrganicSynthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, andKocienski, Protective Groups, Thieme Verlag, New York, N.Y., 1994, whichare incorporated herein by reference for such disclosure).

Examples can be made using known techniques and further chemicallymodified, in some embodiments, to facilitate intranuclear transfer to,e.g., a splicing complex component, a spliceosome or a premRNA molecule.One of ordinary skill in the art will appreciate the standard medicinalchemistry approaches for chemical modifications for intranucleartransfer (e.g., reducing charge, optimizing size, and/or modifyinglipophilicity).

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein. The starting materialsand reagents used for the synthesis of the compounds described hereinmay be synthesized or can be obtained from commercial sources, such as,but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and FischerScientific.

Stereochemistry: (±) indicates that the product is a racemic mixture ofenantiomers. For example (±) (1S,2S,3R,5R) indicates that the relativeproduct stereochemistry shown is based on known stereochemistry ofsimilar compounds and or reactions and the product is a racemic mixtureof enantiomers of both (1S,2S,3R,5R) and (1R,2R,3S,5S) stereoisomers.

A compound in which the absolute stereochemistry of separatedenantiomers is undetermined is represented as being either of the singleenantiomers, for example (1S,2S,3R,5R) or (1R,2R,3S,5S) or drawn asbeing either possible single enantiomer. In such cases, the product ispure and a single enantiomer, but absolute stereochemistry is notidentified, but relative stereochemistry is known and indicated.

Amine Intermediates:

Synthesis of (±) tert-butyl(1S,2R,3R,5R)-2-fluoro-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate(INT-1)

Step 1: Synthesis of (±) tert-butyl(1S,5R)-3-((trimethylsilyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate.TMSCl (19.2 g, 17.8 mmol) and triethylamine (25 mL) was added to astirred solution of tert-butyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (20 g, 8.89 mmol) in 270mL of DMF. The mixture was stirred at 100° C. for 16 h. Water (300 mL)was added to the reaction, then the mixture was extracted with ethylacetate (100 mL×3). The combined organic phases were dried andconcentrated, then purified by silica gel chromatography (10%EtOAc/petroleum ether) to give the title compound (21 g, 79% yield).LCMS: m/z 298.2 [M+H]⁺; t_(R)=2.33 min.

Step 2: Synthesis of (±) tert-butyl(1S,2S,5S)-2-fluoro-8-aza-bicyclo[3.2.1]octan-3-one. Selectfluor (14.16g, 40 mmol) was added to a solution of (±) tert-butyl3-((trimethylsilyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (6 g,20 mmol) in 120 mL of dry CH₃CN at 0° C. After addition, the mixture wasstirred at room temperature for 2 h. The mixture was concentrated, thenpurified by silica gel chromatography (50% EtOAc/petroleum ether) togive the title compound. (3.84 g, 78% yield). LCMS: m/z 188.2 [M−55]⁺;t_(R)=1.86 min.

Step 3: Synthesis of (±) tert-butyl(1S,2R,3R,5R)-3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate.A mixture of (±) tert-butyl(1S,2S,5S)-2-fluoro-8-aza-bicyclo[3.2.1]octan-3-one (10 g, 41 mmmol) andbenzylamine (7.6 g, 82 mmol) in 160 mL of toluene was refluxed for 4 h.The mixture was concentrated. 160 mL of methanol was added. NaBH₄ (3.1g, 82 mmol) was added in small portions at 0° C. The mixture was stirredfor 2 h at room temperature and concentrated. H₂O (80 mL) was added andthe resulting mixture was extracted with EtOAc (60 mL×3). The combinedorganic solvents were dried over anhydrous Na₂SO₄, concentrated andpurified on silica gel chromatography (10-50% EtOAc/petroleum ether) toyield the title compound as a white solid (7.3 g, 53% yield). LCMS: m/z335.1 [M+H]⁺; t_(R)=1.80 min.

Step 4: Synthesis of (±) tert-butyl(1S,2R,3R,5R)-3-(benzyl(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylateTo a solution of (±) tert-butyl(1S,2R,3R,5R)-3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(800 mg, 2.395 mmol, 1 equiv) in MeOH (100 ml) was added formaldehyde(143 mg, 4.8 mmol). The reaction mixture was stirred at room temperaturefor 0.5 h, then NaBH₃CN (301 mg, 4.8) was added. The mixture was stirredfor additional 3 h, monitored by LCMS. Solvent was evaporated and theresulting crude was purified by column chromatography on silica gelchromarography (50% EtOAc/petroleum ether) to yield the title compound(800 mg, 2.30 mmol, 96% yield) as white powder. LCMS: m/z 349.1 [M+H]⁺;t_(R)=1.42 min.

Step 5: Synthesis of (±) tert-butyl(1S,2R,3R,5R)-2-fluoro-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate(INT-1). To a solution of (±) tert-butyl(1S,2R,3R,5R)-3-(benzyl(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(800 mg, 1 equiv) in EtOH (100 mL) was added Pd/C (80 mg, 10%). Thereaction mixture was stirred under H2 atmosphere for 2 h and monitoredby LCMS. The mixture was filtered and the filtrate was concentratedunder reduced pressure to give the title compound (500 mg, 84% yield) ascolorless oil, which was directly used in next step. LCMS: m/z 203.1[M−55]⁺; t_(R)=1.19 min.

Synthesis of (±) tert-butyl(1S,2R,3R,5R)-3-((6-chloropyridazin-3-yl)(cyclopropyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(INT-2)

Step 1: Synthesis of (±) tert-butyl(1S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(INT-2). A mixture of (±) tert-butyl(1S,2R,3R,5R)-3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(3 g, 9.0 mmol) and Pd/C (2 g, 10% on activated carbon) in EtOAc (80 mL)was degassed and stirred at room temperature for 16 h under hydrogenatmosphere. The reaction mixture was filtered and the filtrate wasconcentrated to give the title compound (2 g, 91% yield) as a yellowoil, which was used directly in next step. LCMS: m/z 189.2 [M+H]⁺;t_(R)=1.53 min.

Synthesis of (±) tert-butyl(1S,2S,3R,5R)-2-fluoro-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate(INT-3)

Step 1: Synthesis of tert-butyl3-((trimethylsilyl)oxy)-9-azabicyclo[3.3.1]non-2-ene-9-carboxylate.

Chlorotrimethylsilane (34 g, 314 mmol) was added to a stirred solutionof tert-butyl 3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (50 g, 209.2mmol) and Et₃N (42 g, 418.4 mmol) in 500 mL of DMF at 0° C. undernitrogen protection. After the addition, the mixture was then stirred at100° C. for 18 h. The mixture was cooled to room temperature, quenchedwith H₂O (500 mL) and extracted with EtOAc (200 mL×3). The combinedorganic solvents were washed with brine (100 mL), dried over anhydrousNa₂SO₄, concentrated and purified by silica gel column (0-5%EtOAc/petroleum ether) to give the title compound as colorless oil (46g, 71% yield). LCMS: m/z 212.3 [M−100]⁺; t_(R)=2.32 min.

Step 2: Synthesis of (±) tert-butyl(1S,2S,5R)-2-fluoro-3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate.Selectfluor (62.8 g, 177.5 mmol) was added in three portions to astirred solution of tert-butyl3-((trimethylsilyl)oxy)-9-azabicyclo[3.3.1]non-2-ene-9-carboxylate (46g, 147.9 mmol) in CH₃CN (460 mL) at 0° C. under N₂. The mixture wasstirred at room temperature 3 h, quenched with H₂O (400 mL) andextracted with EtOAc (300 mL×3). The combined organic solvents wereconcentrated and purified by silica gel chromatography (0-10%EtOAc/petroleum ether) to give the title compound as white solid (19g,50% yield). LCMS: m/z 202.1 [M−55]⁺; t_(R)=1.86 min.

Step 3: Synthesis of (±) tert-butyl(1S,2S,3R,5R)-2-fluoro-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate(INT-3)

Lithium tri-sec-butylborohydride (40 mL, 40 mmol, 1N solution in THF)was added to a solution of (±) tert-butyl(1S,2S,5R)-2-fluoro-3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (4 g,15.56 mmol) in anhydrous THF (40 mL) at −78° C. After the addition, themixture was stirred at −78° C. for 2 h. Water (100 mL) was added toquench the reaction. The mixture was concentrated, extracted with ethylacetate (100 mL×3), the organic layers were combined, dried overanhydrous Na₂SO₄, and concentrated. The residue was purified by silicagel chromatography eluting with 0-20% EtOAc/petroleum ether to give thetitle compound (3.5 g, 87% yield) as a white solid. LCMS: m/z 204.1[M−55]⁺; t_(R)=1.02 min.

Compound Examples

Chiral SFC Purification Conditions: All methods: Column Temp = 35° C.,Back pressure = 100 bar; Detection Wavelength 214 nM Cycle InjectionMethod Column Mobile Phase Flow Rate Time Volume SFC-A IG 20*250 mm,CO₂/MeOH (0.2% Methanol 130 g/min 5.9 min 2.5 mL 10 μm (Daicel) Ammonia)= 60/40

Example 1 Synthesis of4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-oneand4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one(Compound 1A and Compound 1B)

Step 1: Synthesis of methyl2-[(4-bromo-2-methoxyphenyl)formamido]acetate

Into a 10 L round-bottom flask, was placed 4-bromo-2-methoxybenzoic acid(250 g, 1082 mmol, 1.0 equiv), methyl 2-aminoacetate (106.0 g, 1.19 mol,1.10 equiv), EDCI (415 g, 2.15 mol, 2.0 equiv), HOBT (29.24 g, 216.4mmol, 0.20 equiv), DIPEA (420 g, 3.25 mol, 3.00 equiv) and DCM (2.5L).The resulting solution was stirred for 2 h at room temperature. Thereaction was then quenched by the addition of 2 L of water/ice. Theresulting solution was extracted with 2×2 L of DCM and the organiclayers were combined, dried over Na₂SO₄, and concentrated under vacuumto give the title compound (280 g, 85.7%) as a white solid which wasused without further purification in the next step. LCMS: m/z 302.0,304.0; [M+H]⁺; t_(R)=1.0 min.

Step 2: Synthesis of methyl2-[(4-bromo-2-methoxyphenyl)methanethioamido]acetate

Into a 2.5 L round-bottom flask, was placed methyl2-[(4-bromo-2-methoxyphenyl)formamido]acetate (170 g, 563 mmol, 1.0equiv), toluene (1.0 L), and2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (113.8g, 281.3 mmol, 0.50 equiv). The resulting solution was stirred for 2 hat 100° C. Then the reaction mixture was cooled to 0° C. and the solidswere collected by filtration to give the title compound (120 g, 67.0%)as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 10.07 (s, 1H), 8.49 (d,J=8.5 Hz, 1H), 7.22 (dd, J=8.6, 1.8 Hz, 1H), 7.14 (d, J=1.8 Hz, 1H),4.62 (d, H=4.2 Hz, 2H), 4.03 (s, 3H), 3.87 (s, 3H). LCMS: m/z 318.0,320.0 [M+H]⁺; t_(R)=1.28 min.

Step 3: Synthesis of (±) tert-butyl(1S,2R,3R,5R)-3-((6-(4-bromo-2-hydroxyphenyl)-1,2,4-triazin-3-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 2.5 L round-bottom flask, was placed ethyl2-[(4-bromo-2-ethoxyphenyl)methanethioamido]acetate (120.0 g, 361 mmol,1.00 equiv), hydrazine hydrate (80%) (87.8 mL, 1.75 mol, 5.00 equiv),EtOH (750 mL). The resulting solution was stirred for 2 h at 80° C. Theresulting mixture was concentrated under vacuum to give the titlecompound (100 g, 97.4%) as a yellow solid. LCMS: m/z 283.9, 285.9[M+H]⁺; t_(R)=0.81 min.

Step 4: Synthesis of3-(4-bromo-2-methoxyphenyl)-6-chloro-4,5-dihydro-1,2,4-triazine

Into a 2-L round-bottom flask, was placed3-(4-bromo-2-methoxyphenyl)-4,5-dihydro-1H-1,2,4-triazin-6-one (100 g,1.0 equiv) and POCl₃ (700 mL). The resulting solution was stirred for 2h at 100° C. The reaction mixture was cooled to room temperature andthen concentrated in vacuo. To the crude product was added toluene andthe solution was concentrated in vacuo. This operation was repeatedthree times to remove POCl₃, and afforded the crude title compound (100g, 93.9%) as a dark brown solid which was used without furtherpurification in the next step.

Step 5: Synthesis of 3-(4-bromo-2-methoxyphenyl)-6-chloro-1,2,4-triazine(INT-4)

Into a 2-L round-bottom flask, was placed3-(4-bromo-2-methoxyphenyl)-6-chloro-4,5-dihydro-1,2,4-triazine (100.0g, 331 mmol, 1.00 equiv), and DMF (1.0 L). The flask was cooled in anice bath and manganese dioxide (287.3 g, 3.31 mmol, 10.0 equiv) wasadded slowly in portions. The resulting solution was stirred at 50° C.overnight, then the reaction mixture was filtered over Celite® brandfilter agent. The filter cake was washed with ethyl acetate, thefiltrate was combined and washed twice with water, twice with brine,dried over sodium sulfate, and concentrated in vacuo. The residue waspurified by silica gel flash chromatography with a gradient ofEtOAc/petroleum ether (0 to 30 percent) to give the title compound (15g, 15.1%) as a red solid. LCMS: m/z 301.9 [M+H]⁺; t_(R)=1.50 min.

Step 6: Synthesis of (±) tert-butyl(1S,2R,3R,5R)-3-((3-(4-bromo-2-methoxyphenyl)-1,2,4-triazin-6-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 250-mL round-bottom flask, was placed3-(4-bromo-2-methoxyphenyl)-6-chloro-1,2,4-triazine (10.0 g, 33.3 mmol,1.00 equiv), (±) tert-butyl(1S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(INT-2, 8.13 g, 33.3 mmol, 1.00 equiv), DMSO (100 mL), and DIPEA (8.60g, 66.5 mmol, 2.00 equiv). The resulting solution was stirred overnightat 120° C. The reaction was then quenched by the addition of 200 mL ofwater/ice, extracted with 2×200 ethyl acetate, the organic layerscombined, and concentrated under vacuum. The residue was purified bysilica gel chromatography eluting with ethyl acetate/hexane (1:3) togive the title compound (3.5 g, 20.7%) as a yellow solid. LCMS: m/z508.2, 510.2 [M+H]⁺; t_(R)=1.47 min.

Step 7: Synthesis of (±) tert-butyl(1S,2R,3R,5R)-3-((3-(4-bromo-2-methoxyphenyl)-1,2,4-triazin-6-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(INT-5)

Into a 100-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placed the mixture of (±) tert-butyl(1S,2R,3R,5R)-3-[[3-(4-bromo-2-methoxyphenyl)-1,2,4-triazin-6-yl]amino]-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(3.50 g, 6.88 mmol, 1.00 equiv) and DMF (35 mL). The solution was cooledto 0° C. and NaH (0.20 g, 8.33 mmol, 1.21 equiv) was added slowly. Thenthe solution was stirred for 15 min at 0° C. then CH₃I (1.27 g, 8.95mmol, 1.30 equiv) was added slowly at 0° C. The resulting solution wasallowed to stir an additional 1 h at 0° C. The reaction was thenquenched by the addition of 100 mL of water. The resulting solution wasextracted with 3×200 mL of ethyl acetate concentrated under vacuum. Theresidue was purified by silica gel chromatography eluting with ethylacetate/hexane (1:4) to give the title compound (2.0 g, 55.6%) as ayellow solid. LCMS: m/z 522.3, 524.3 [M+H]⁺; t_(R)=0.88 min.

Step 8: Synthesis of tert-butyl(1S,2R,3R,5R)-2-fluoro-3-([3-[2-methoxy-4-(1-methyl-2-oxopyridin-4-yl)phenyl]-1,2,4-triazin-6-yl](methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylateand tert-butyl(1R,2S,3S,5S)-2-fluoro-3-([3-[2-methoxy-4-(1-methyl-2-oxopyridin-4-yl)phenyl]-1,2,4-triazin-6-yl](methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(PENT-1A and PENT-1B)

Into a 40-mL vial, was placed (±) tert-butyl(1S,3R,5R)-3-[[3-(4-bromo-2-methoxyphenyl)-1,2,4-triazin-6-yl](methyl)amino]-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate (1 g,1.914 mmol, 1.00 equiv), 1-methyl-2-oxopyridin-4-ylboronic acid (0.44 g,2.871 mmol, 1.50 equiv), Pd(dppf)Cl₂ (0.14 g, 0.191 mmol, 0.10 equiv),K₂CO₃ (0.79 g, 5.743 mmol, 3.00 equiv), dioxane (10.00 mL), and H₂O(2.00 mL). The resulting solution was stirred for overnight at 100° C.Then the reaction was quenched by the addition of 50 mL of water. Theresulting solution was extracted with 2×50 mL of ethyl acetateconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/hexane (1:1) to afford the title compoundwhich was further purified by Chiral-Prep-HPLC purification with thefollowing conditions (NB-Prep Chiral HPLC-01): Column, CHIRALPAK IA,2*25 cm,5 μm; mobile phase, hexame:MTBE=1:1(10mM NH₃) and EtOH (hold 50%EtOH—in 21 min) to give PENT-1A (t_(R)=2.26 min, 170 mg, 16.1%) andPENT-1B (t_(R)=4.45 min, 170 mg, 16.1%) as white solids. PENT-1A LCMS:m/z 551.4 [M+H]⁺; t_(R)=1.40 min. PENT-1B LCMS: m/z 551.4 [M+H]⁺;t_(R)=1.40 min.

Step 8: Synthesis of4-[4-(6-[[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino]-1,2,4-triazin-3-yl)-3-hydroxyphenyl]-1-methylpyridin-2-oneand 4-[4-(6-[[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino]-1,2,4-triazin-3-yl)-3-hydroxyphenyl]-1-methylpyridin-2-one(Compound 1A and Compound 1B)

Into an 8-mL vial, was placed PENT-1A (80 mg, 0.15 mmol, 1.0 equiv) and(BBr₃ 1.0 M in 1,4-dioxane, 5.0 mL). The resulting solution was stirredfor 3 h at room temperature. Then the reaction was then quenched by theaddition of 20 mL of water and pH was adjusted to 9-10 with NaHCO₃. Theresulting solution was extracted with 2×50 mL of ethyl acetate then thecombined organic layers concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions (NB-Prep-HPLC-01):Column, XBridge Prep C18 OBD Column, 5 um, 19×150 mm; mobile phase,Water(10 MMOL/L NH₄HCO₃) and ACN (20% PhaseB up to 38% in 10 min) togive the title compound as Compound 1A (30 mg, 46.10%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 13.82 (s, 1H), 8.98 (d, J=42.9 Hz, 1H),8.46-8.16 (m, 1H), 7.79 (d, J=7.1 Hz, 1H), 7.34 (d, J=31.1 Hz, 2H),6.86-6.48 (m, 2H), 5.25-5.150 (m, 1H), 4.76-4.66 (m, 1H), 3.60 (s, 2H),3.46 (s, 3H), 3.20 (d, J=10.0 Hz, 3H), 2.27 (t, J=12.9 Hz, 1H), 1.89 (s,2H), 1.74 (d, J=16.8 Hz, 2H), 1.59 (d, J=12.2 Hz, 1H). LCMS: m/z 437.2[M+H]⁺; t_(R)=1.06 min.

Following the procedure above, but with PENT-1B (80 mg, 0.15 mmol), gavethe title compound as Compound 1B (30 mg, 46.1% yield) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 13.82 (s, 1H), 8.98 (d, J=42.9 Hz, 1H),8.46-8.16 (m, 1H), 7.79 (d, J=7.1 Hz, 1H), 7.34 (d, J=31.1 Hz, 2H),6.86-6.48 (m, 2H), 5.25-5.150 (m, 1H), 4.76-4.66 (m, 1H), 3.60 (s, 2H),3.46 (s, 3H), 3.20 (d, J=10.0 Hz, 3H), 2.27 (t, J=12.9 Hz, 1H), 1.89 (s,2H), 1.74 (d, J=16.8 Hz, 2H), 1.59 (d, J=12.2 Hz, 1H). LCMS: m/z 437.2[M+H]⁺; t_(R)=1.05 min.

Example 2 Synthesis of2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(1H-pyrazol-4-yl)phenoland2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(1H-pyrazol-4-yl)phenol(Compound 2A and Compound 2B)

Step 1. Synthesis of (±)5-bromo-2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)phenol

To a solution of (±) tert-butyl(1S,2R,3R,5R)-3-((3-(4-bromo-2-methoxyphenyl)-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(INT-5, 3.9 g, 7.47 mmol) in CH₂Cl₂ (20 mL) at 25° C. was added BBr₃ (16mL, 1N in CH₂Cl₂) and the reaction was stirred at 25° C. for 2 h, thenwater (15 mL) was added. The organic layer was extracted with water (50mL×2). The combined aqueous layers were adjusted with saturated K₂CO₃aqueous solution to pH to 8-9 and extracted with dichloromethane/MeOH(240 mL, 10:1, v/v). The organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated to give the title compound (3.7 g) asa yellow solid, which was used directly in the next step. LCMS: m/z410.0 [M+H]⁺; t_(R)=1.86 min.

Step 2: Synthesis of (±) tert-butyl(1S,2R,3R,5R)-3-((3-(4-bromo-2-((tert-butoxycarbonyl)oxy)phenyl)-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate

Di-tert-butyl dicarbonate (8.33 mL, 36.25 mmol) and DIPEA (9.0 mL, 54.4mmol) were added to a solution of (±)5-bromo-2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)phenol(3.7 g, 9.06 mmol) in dioxane (60 ml). The mixture was then stirred at50° C. for 16 h. The reaction mixture was concentrated and the residuepurified with silica gel chromatography (10-50% EtOAc/petroleum ether)to give the title compound (1.96 g, 3.03 mmol, 33.5% yield). LCMS: m/z608.1, 610.1 [M+H]⁺; t_(R)=2.31 min.

Step 3. Chiral Separation to Isolate tert-butyl(1S,2R,3R,5R)-3-((3-(4-bromo-2-((tert-butoxycarbonyl)oxy)phenyl)-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylateand tert-butyl(1R,2S,3S,5S)-3-(4-bromo-2-((tert-butoxycarbonyl)oxy)phenyl)-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(HETX-2A and HETX-2B)

Racemic intermediate, (±) tert-butyl(1S,2R,3R,5R)-3-((3-(4-bromo-2-((tert-butoxycarbonyl)oxy)phenyl)-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate,1.96 g, was purified by chiral SFC purification to give the two titlecompounds as HETX-2A (t_(R)=1.32 min, 880 mg) and HETX-2B (t_(R)=2.02min, 900 mg).

Instrument: SFC-200 (Thar, Waters); Column: IG 20*250 mm, 10 um(Daicel); Column temperature: 35° C.; Mobile phase: CO₂/MeOH(0.2%methanol Ammonia)=60/40; Flow rate: 130 g/min; Back pressure: 100 bar;Detection wavelength: 214 nm; Cycle time: 5.9 min; Sample solution:1960mg dissolved in 50 ml Methanol; Injection volume: 2.5 mL

Step 4: Synthesis of2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(1H-pyrazol-4-yl)phenoland2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(1H-pyrazol-4-yl)phenol(Compound 2A and Compound 2B)

A mixture of HETX-2A (200 mg, 0.33 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (96 mg, 0.49mmol), K₃PO₄ (140 mg, 0.66 mmol) and Xphos-Pd-G2 (52 mg, 0.07 mmol) in12 mL of dioxane and 6 mL of H₂O was degassed and stirred at 110° C. for2 h. The mixture was filtered, concentrated and purified on silicacolumn chromatography (0-20% methanol/EtOAc) to yield PENT-2A (120 mg,0.21 mmol, 64.6% yield) as a yellow solid. LCMS: m/z 496.2 [M+H]⁺;t_(R)=1.78 min.

To a solution of PENT-2A (120 mg, 0.21 mmol) in CH₂Cl₂ (6 mL) at 25° C.was added HCl (4 mL, 4N in dioxane) and the reaction was stirred at 25°C. for 1 h. Then the mixture was concentrated, and the residue wasdissolved into water (3 mL). The solution was neutralized with saturatedK₂CO₃ aqueous solution, and the precipitate was collected by filtration,washed with water and dried under reduced pressure to give the titlecompound as Compound 2A (36 mg, 0.091 mmol, 43.3% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (s, 1H), 8.77 (d, J=9.0 Hz,1H), 8.15-8.12 (m, 3H), 7.27-7.25 (m, 2H), 4.92-4.81 (m, 1H), 4.73-4.60(m, 1H), 3.52-3.48 (m, 2H), 3.12 (s, 3H), 2.42-2.38 (m, 1H), 2.28-2.21(m, 1H), 1.78-1.51 (m, 5H). LCMS: m/z 396.1 [M+H]⁺; t_(R)=1.27 min.

Following the two-step procedure above, but starting with HETX-2B (200mg, 0.33 mmol) gave the title compound as Compound 2B (25 mg, 19%overall yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (s,1H), 8.77 (d, J=9.0 Hz, 1H), 8.15-8.12 (m, 3H), 7.27-7.25 (m, 2H),4.92-4.81 (m, 1H), 4.73-4.60 (m, 1H), 3.52-3.48 (m, 2H), 3.12 (s, 3H),2.42-2.38 (m, 1H), 2.28-2.21 (m, 1H), 1.78-1.51 (m, 5H). LCMS: m/z 396.1[M+H]⁺; t_(R)=1.27 min.

The examples in Table 6 were synthesized using a sequence analogous tothat used to synthesize Examples 2A and 2B general Scheme 2 above:

TABLE 6 Additional Compounds made following General Method B (Scheme 2)and Example 2. Chiral Chiral Intermediate SFC Retention LCMSPurification Time Compound Structure Proton NMR M + H Method (min) 3A

1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.78 (s, 1H), 8.23 (s, 1H),8.13 (d, J = 8.7 Hz, 1H), 7.94 (s, 1H), 7.21-7.20 (m, 2H), 4.91-4.81 (m,1H), 4.73- 4.60 (m, 1H), 3.87 (s, 3H), 3.55-3.51 (m, 2H), 3.12 (s, 3H),2.42-2.38 (m, 1H), 2.28-2.21 (m, 1H), 1.78-1.51 (m, 5H) 410 SFC-A 1.333B

1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.78 (s, 1H), 8.23 (s, 1H),8.14-8.11 (m, 1H), 7.94 (s, 1H), 7.22-7.19 (m, 2H), 4.91-4.81 (m, 1H),4.73-4.60 (m, 1H), 3.87 (s, 3H), 3.55-3.51 (m, 2H), 3.12 (s, 3H),2.28-2.21 (m, 1H), 1.78-1.51 (m, 5H) 410 SFC-A 2.03

Example 3 Synthesis of6-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(methoxymethoxy)-N,N-dimethylbenzofuran-2-carboxamideand6-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-(methoxymethoxy)-N,N-dimethylbenzofuran-2-carboxamide(Compound 4A and 4B)

Step 1: Synthesis of 6-bromo-3-chloro-1,2,4-triazine

Into a 200-mL vial, was placed 6-bromo-1,2,4-triazin-3-amine (5.00 g,28.6 mmol, 1.0 equiv), CuCl₂ (5.00 g, 37.15 mmol, 1.30 equiv), MeCN (50mL), and tert-butyl nitrite (4.7 g, 45.6 mmol, 1.60 equiv). Theresulting solution was stirred for 2 h at 70° C., then concentratedunder vacuum. The residue was purified by silica gel chromatographyeluting with ethyl acetate/hexane (1:10) to provide the title compound(2.5 g, 45% yield) as a light yellow solid.

Step 2: Synthesis of (±) tert-butyl(1S,2R,3R,5R)-3-((3-chloro-1,2,4-triazin-6-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 200-mL vial was placed 6-bromo-3-chloro-1,2,4-triazine (2.5 g,12.9 mmol, 1.0 equiv), (±) tert-butyl(1S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(3.14 g, 12.86 mmol, 1.00 equiv), DIPEA (3.32 g, 25.7 mmol, 2.00 equiv)and DMSO (50 mL). The resulting solution was stirred for 2 h at 60° C.The reaction was then quenched by the addition of 20 mL of water/ice.The resulting solution was extracted with 3×100 mL of ethyl acetateconcentrated under vacuum. The residue was purified by silica gelchromatography eluting with ethyl acetate/hexane (1:3) to provide a 1:1mixture of (±) tert-butyl(1S,2R,3R,5R)-3-[(3-chloro-1,2,4-triazin-6-yl)amino]-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylateand (±) tert-butyl(1S,3R,5R)-3-[(6-bromo-1,2,4-triazin-3-yl)amino]-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylateas a yellow solid which was carried forward into the next step withoutfurther purification. LCMS title compound: m/z 302.1 [M−tBu+H]⁺;t_(R)=2.46 min.

Step 3: Synthesis of (±) tert-butyl(1S,2R,3R,5R)-3-((3-chloro-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 200-mL vial purged and maintained with an inert atmosphere ofnitrogen was placed a 1:1 mixture of (±) tert-butyl(1S,2R,3R,5R)-3-[(3-chloro-1,2,4-triazin-6-yl)amino]-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylateand (±) tert-butyl(1S,2R,3R,5R)-3-[(6-bromo-1,2,4-triazin-3-yl)amino]-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(2.5 g, 6.58 mmol, 1.00 equiv), DMF (10.00 mL). The solution was stirredat 0° C. and NaH (60 wt % in mineral oil, 205 mg, 8.56 mmol, 1.30 equiv)was added slowly. Then the solution was stirred 15 min at 0° C. thenCH₃I (1.40 g, 9.87 mmol, 1.50 equiv) was added slowly at 0° C. Theresulting solution was stirred an additional 1 h at 0° C. The reactionwas then quenched by the addition of 50 mL water, extracted with ethylacetate (3×50 mL), the organic layers combined, and concentrated undervacuum. The residue was purified by silica gel chromatography elutingwith ethyl acetate/hexane (1:3) to provide a mixture of3-chloro-1,2,4-triazin-6-yl and 6-bromo-1,2,4-triazin-3-yl products. Theproduct was further purified by SFC purification. SFC conditions:Column: CHIRAL ART Cellulose-SB, 2*25 cm,5 um; Mobile Phase A:CO₂,Mobile Phase B:MeOH-HPLC; Flow rate:45 mL/min; Gradient:15% B; 254 nm;RT1:3.8 min; RT2:4.6 min; Injection Volume: 0.4 mL. This resulted in and900 mg of the title compound as a yellow solid. LCMS: m/z 316.0[M−tBu+H]⁺; t_(R)=1.28 min.

Step 4: Synthesis of tert-butyl(1S,2R,3R,5R)-3-((3-(2-(dimethylcarbamoyl)-5-(methoxymethoxy)benzofuran-6-yl)-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylateand tert-butyl(1R,2S,3S,5S)-3-(2-(dimethylcarbamoyl)-5-(methoxymethoxy)benzofuran-6-yl)-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(PENT-4A and PENT-4B)

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placed (±) tert-butyl(1S,2R,3R,5R)-3-[(3-chloro-1,2,4-triazin-6-yl)(methyl)amino]-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(250 mg, 0.67 mmol, 1.00 equiv),5-(methoxymethoxy)-N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-carboxamide(328 mg, 0.874 mmol, 1.30 equiv), Pd(dppf)Cl₂ (24.6 mg, 0.034 mmol, 0.05equiv), K₂CO₃ (186 mg, 1.35 mmol, 2.00 equiv), dioxane (5.00 mL), andH₂O (1.00 mL). The resulting solution was stirred for 3 h at 100° C.,then concentrated under vacuum. The residue was purified by silica gelflash chromatography eluting with ethyl acetate/petroleum ether (3:1) toprovide the crude product.

Step 5: Chiral Purification to Isolate tert-butyl(1S,2R,3R,5R)-3-((3-(2-(dimethylcarbamoyl)-5-(methoxymethoxy)benzofuran-6-yl)-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylateand tert-butyl(1R,2S,3S,5S)-3-(2-(dimethylcarbamoyl)-5-(methoxymethoxy)benzofuran-6-yl)-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate(PENT-4A & PENT-4B)

The product from above, (±) tert-butyl(1S,2R,3R,5R)-3-((3-(2-(dimethylcarbamoyl)-5-(methoxymethoxy)benzofuran-6-yl)-1,2,4-triazin-6-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylatewas purified by Chiral-Prep-HPLC with the following conditions(Prep-HPLC-004): Column, CHIRAL ART Cellulose-SB, 2*25 cm,5 um; mobilephase, Hex:MtBE=1:1(10 mM NH₃) and EtOH— (hold 20% EtOH— in 22 min). Thepurification resulted in two enantiomeric products (PENT-4A (t_(R)=2.75min, 100 mg, 25.4% yield over 2 steps) and PENT-4B (t_(R)=3.09 min, 100mg, 25.4% yield over two steps) as yellow solids. PENT-4A: LCMS: m/z585.3 [M+H]⁺; t_(R)=1.83 min. PENT-4B: LCMS: m/z 585.3 [M+H]⁺;t_(R)=1.83 min.

Step 5: Synthesis6-(6-(((4S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-hydroxy-N,N-dimethylbenzofuran-2-carboxamideand6-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-5-hydroxy-N,N-dimethylbenzofuran-2-carboxamide(Compound 4A and Compound 4B)

Into an 8-mL vial, was PENT-4A (100 mg, 1 equiv), HCl (gas) in1,4-dioxane (5.0 mL). The resulting solution was stirred for 2 h at roomtemperature, then the reaction was concentrated under vacuum. The crudeproduct was purified by Prep-HPLC with the following conditions(NB-Prep-HPLC-01): Column, XBridge Shield RP18 OBD Column, 5 um, 19*150mm; mobile phase, Water (10 MMOL/L NH₄HCO₃) and ACN (24% PhaseB up to35% in 10 min) to provide the title compound as Compound 4A (25 mg,33.22%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.09 (s, 1H),8.04 (s, 1H), 7.30 (d, J=0.9 Hz, 1H), 7.21 (s, 1H), 5.18 (d, J=37.4 Hz,1H), 4.71 (d, J=51.5 Hz, 1H), 3.69 (s, 2H), 3.40 (s, 3H), 3.30 (d, J=1.7Hz, 3H), 3.16 (s, 3H), 2.49-2.39 (m, 1H), 2.00 (s, 2H), 1.86 (t, J=7.9Hz, 2H), 1.77-1.65 (m, 1H). LCMS: m/z 441.2 [M+H]⁺; t_(R)=1.20 min.

Following the procedure above, but with PENT-4B (100 mg, 0.17 mmol) gavethe title compound Compound 4B (25 mg, 33% yield) as a yellow solid. ¹HNMR (300 MHz, Methanol-d4) δ 9.15 (s, 1H), 8.06 (s, 1H), 7.31 (d, J=0.9Hz, 1H), 7.23 (s, 1H), 5.48-5.25 (m, 1H), 5.14 (d, J=48.7 Hz, 1H), 4.33(d, J=22.8 Hz, 2H), 3.40 (s, 3H), 3.17 (s, 3H), 2.78-2.68 (m, 1H), 2.25(d, J=9.0 Hz, 4H), 2.07 (d, J=14.3 Hz, 1H). LCMS: m/z 441.2 [M+H]⁺;t_(R)=1.19 min.

Scheme 4: General Synthesis Method D: Heterocycle Suzuki and ChiralPurification of Penultimate Intermediates, Hydroxy

Example 4 Synthesis of2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenoland2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol(Compound 5A and Compound 5B)

Step 1: Synthesis of 5-bromo-2-(6-chloro-1,2,4-triazin-3-yl)phenol

To a solution of 3-(4-bromo-2-methoxyphenyl)-6-chloro-1,2,4-triazine(INT-4, 550 mg, 1.83 mmol) in CH₂Cl₂ (5 mL) was added BBr₃ (3 mL, 1N inCH₂Cl₂) and the mixture was stirred at room temperature for 1 h. Thereaction was quenched with water (5 ml). Then pH value was adjusted to9-10 with K₂CO₃ aqueous solution. The mixture was extracted withCH₂Cl₂/MeOH (5:1, v/v) (70 mL×3), the organic layers combined, washedwith little brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give the title compound (500 mg, 95% yield) as apink solid, which was used directly to next step without furtherpurification. LCMS: m/z 288.0 [M+H]⁺; t_(R)=2.23 min.

Step 2: Synthesis of (±) tert-butyl(1S,2S,3R,5R)-3-((3-(4-bromo-2-hydroxyphenyl)-1,2,4-triazin-6-yl)oxy)-2-fluoro-9-azabicyclo[3.3.1]nonane-9-carboxylate

To a solution of (±) tert-butyl(1S,2S,3R,5R)-2-fluoro-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate(INT-3, 563 mg, 2.2 mmol) in THF (10 mL) was added NaH (176 mg, in 60%of mineral oil, 4.41 mmol). After stirring at room temperature for 1 h,5-bromo-2-(6-chloro-1,2,4-triazin-3-yl)phenol (420 mg.1.47 mmol) wasadded. The mixture was stirred for 8 h, quenched with water, extractedwith CH₂Cl₂ (3×80 mL) and the combined organic layers were washed withwater, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith 30% EtOAc/petroleum ether to give the title compound (400 mg, 62%yield) as a white solid. LCMS: m/z 509.0 [M+H]⁺; t_(R)=2.39 min.

Step 3: Synthesis of (±) tert-butyl(1S,2S,3R,5R)-2-fluoro-3-(2-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,2,4-triazin-6-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate

A mixture of (±) tert-butyl(1S,2S,3R,5R)-3-((3-(4-bromo-2-hydroxyphenyl)-1,2,4-triazin-6-yl)oxy)-2-fluoro-9-azabicyclo[3.3.1]nonane-9-carboxylate(400 mg, 0.78 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(208 mg, 1 mmol), Pd(dppf)Cl₂ (57 mg, 0.078 mmol) and K₂CO₃ (215 mg,1.56 mmol) in dioxane (8 mL) and water (1 mL) was degassed with N₂ andheated at 105° C. for 1.5 h under N₂. After cooling to room temperature,the reaction was concentrated and purified by silica gel flashchromatography eluting with 70% EtOAc/petroleum ether to give the titlecompound (200 mg, 50% yield) as a white solid. LCMS: m/z 511.2 [M+H]⁺;t_(R)=1.97 min.

Step 4: Chiral Purification to Isolate tert-butyl(1S,2S,3R,5R)-2-fluoro-3-((3-(2-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,2,4-triazin-6-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylateand tert-butyl(1R,2R,3S,5S)-2-fluoro-3-((3-(2-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,2,4-triazin-6-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate(PENT-5A & PENT-5B)

(±) tert-butyl(1S,2S,3R,5R)-2-fluoro-3-((3-(2-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,2,4-triazin-6-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate,200 mg, was purified by chiral SFC purification by the following methodto give the two title compounds (PENT-5A, t_(R)=1.14 min, 80 mg) and(PENT-5B, t_(R)=1.42 min, 45 mg) as white solids.

Instrument: SFC-150 (Waters); Column: IC 20*250 mm, 10 um (Daicel);Column temperature: 35° C.; Mobile phase: CO2/(MeOH:ACN=1:1)=40/60; Flowrate: 120 g/min; Back pressure: 100 bar; Detection wavelength: 214 nm;Cycle time: 3 min; Sample solution: 200 mg dissolved in 60 mL Methanoland Dichloromethane; Injection volume: 1.9 mL.

Step 5: Synthesis of2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenoland2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-1,2,4-triazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol(Compound 5A and Compound 5B)

To a solution of (PENT-5A, 80 mg, 0.16 mmol) in CH₂Cl₂ (10 mL) was added4N HCl in dioxane (3 mL). The mixture was stirred at room temperaturefor 2 h, concentrated to dryness, then saturated K₂CO₃ aqueous solutionwas added until pH of 7-8. The solid was collected by filtration anddried under reduced pressure to give the title compound as Compound 5A(41 mg, 64% yield) as a white solid. ¹H NMR (400 MHz, Methanol-d₄) δ8.61 (s, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.06 (s, 1H), 7.90 (s, 1H),7.23-7.17 (m, 2H), 6.12-5.90 (m, 1H), 5.17-4.99 (m, 1H), 3.96 (s, 3H),3.55-3.37 (m, 2H), 2.36-2.21 (m, 2H), 2.09-1.96 (m, 2H), 1.90-1.75 (m,4H). LCMS: m/z 411.1 [M+H]⁺; t_(R)=1.29 min.

Following the procedure above but with PENT-5B (45 mg, 0.088 mmol) gavethe title compound as Compound 5B (34 mg, 94% yield) as a white solid.NMR (400 MHz, Methanol-d₄) δ 8.61 (s, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.06(s, 1H), 7.90 (s, 1H), 7.23-7.17 (m, 2H), 6.12-5.90 (m, 1H), 5.17-4.99(m, 1H), 3.96 (s, 3H), 3.55-3.37 (m, 2H), 2.36-2.21 (m, 2H), 2.09-1.96(m, 2H), 1.90-1.75 (m, 4H). LCMS: m/z 411.2 [M+H]⁺; t_(R)=1.29 min.

Additional General Schemes and Examples

Compounds can be made via Scheme 4 wherein5-bromo-2-(6-chloro-1,2,4-triazin-3-yl)phenol A2 (protected orunprotected with G1 protecting group) is coupled with an appropriateamino AA reagent and base to afford A2. Compound A2 can be furthercoupled to a boronic acid or ester BB1 with palladium catalysis, or withHN containing heterocycles with copper catalysis to give A3. Removal ofprotecting groups G1 and G3, if necessary, would give compound A4. It isunderstood that if amine building blocks AA are enantiomeric, thenenantiomeric products can be separated by chiral methods (chiral SFCchromatography, recrystallization, chiral resolution) at any stage ofthe synthesis to provide purified enantiomeric products that can then beindependently carried on through subsequent synthetic steps to provideenantiopure products, including separation of enantiomers of finalproducts.

Compounds can be made via Scheme 5 wherein an appropriate amine buildingblock AA can be added to 3,6-dichloro-1,2,4-triazine mediated by base toafford B1. B1 can then be coupled with a boronic acid or ester BB3, withpalladium catalysis, or with HN containing heterocycles with coppercatalysis to give B2. Removal of protecting groups G1 and G3, ifnecessary, would give compound B3. It is understood that if aminebuilding blocks AA are enantiomeric, then enantiomeric products can beseparated by chiral methods (chiral SFC chromatography,recrystallization, chiral resolution) at any stage of the synthesis toprovide purified enantiomeric products that can then be independentlycarried on through subsequent synthetic steps to provide enantiopureproducts, including separation of enantiomers of final products.

Additional Compounds in Table 7 can be made using the proceduresoutlined in General Schemes 1-5 above.

TABLE 7 Additional Compounds SMSM # Structure 7-1

7-2

7-3

7-4

7-5

7-6

7-7

7-8

7-9

7-10

7-11

7-12

7-13

7-14

7-15

7-16

7-17

7-18

7-19

7-20

7-21

7-22

7-23

7-24

7-25

7-26

7-27

7-28

7-29

7-30

7-31

7-32

7-33

7-34

7-35

7-36

7-37

7-38

7-39

7-40

7-41

7-42

7-43

7-44

7-45

7-46

7-47

7-48

7-49

7-50

7-51

7-52

7-53

7-54

7-55

7-56

7-57

7-58

7-59

7-60

7-61

7-62

7-63

7-64

7-65

7-66

7-67

7-68

7-69

7-70

7-71

7-72

7-73

7-74

7-75

7-76

7-77

7-78

7-79

7-80

7-81

7-82

7-83

7-84

7-85

7-86

7-87

7-88

7-89

7-90

7-91

7-92

7-93

7-94

7-95

7-96

7-97

7-98

7-99

7-100

7-101

7-102

7-103

7-104

7-105

7-106

7-107

7-108

7-109

7-110

7-111

7-112

7-113

7-114

7-115

7-116

7-117

7-118

7-119

7-120

7-121

7-122

7-123

7-124

7-125

7-126

7-127

7-128

7-129

7-130

7-131

7-132

7-133

7-134

7-135

7-136

7-137

7-138

7-139

7-140

7-141

7-142

7-143

7-144

7-145

7-146

7-147

7-148

7-149

7-150

7-151

7-152

7-153

7-154

7-155

7-156

7-157

7-158

7-159

7-160

7-161

7-162

7-163

7-164

7-165

7-166

7-167

7-168

7-169

7-170

7-171

7-172

7-173

7-174

7-175

7-176

7-177

7-178

7-179

7-180

7-181

7-182

7-183

7-184

7-185

7-186

7-187

7-188

7-189

7-190

7-191

7-192

7-193

7-194

7-195

7-196

7-197

7-198

7-199

7-200

7-201

7-202

7-203

7-204

7-205

7-206

7-207

7-208

7-209

7-210

7-211

7-212

7-213

7-214

7-215

7-216

7-217

7-218

7-219

7-220

7-221

7-222

7-223

7-224

7-225

7-226

7-227

7-228

7-229

7-230

7-231

7-232

7-233

7-234

7-235

7-236

7-237

7-238

7-239

7-240

7-241

7-242

7-243

7-244

7-245

7-246

7-247

7-248

7-249

7-250

7-251

7-252

7-253

7-254

7-255

7-256

7-257

7-258

7-259

7-260

7-261

7-262

7-263

7-264

7-265

7-266

7-267

7-268

7-269

7-270

7-271

7-272

7-273

7-274

7-275

7-276

7-277

7-278

7-279

7-280

7-281

7-282

7-283

7-284

7-285

7-286

7-287

7-288

7-289

7-290

7-291

7-292

7-293

7-294

7-295

7-296

7-297

7-298

7-299

7-300

7-301

7-302

7-303

7-304

7-305

7-306

7-307

7-308

7-309

7-310

7-311

7-312

7-313

7-314

7-315

7-316

7-317

7-318

7-319

7-320

7-321

7-322

7-323

7-324

7-325

7-326

7-327

7-328

7-329

7-330

7-331

7-332

7-333

7-334

7-335

7-336

7-337

7-338

7-339

7-340

7-341

7-342

7-343

7-344

7-345

7-346

7-347

7-348

7-349

7-350

7-351

7-352

7-353

7-354

7-355

7-356

7-357

7-358

7-359

7-360

7-361

7-362

7-363

7-364

7-365

7-366

7-367

7-368

7-369

7-370

7-371

7-372

7-373

7-374

7-375

7-376

7-377

7-378

7-379

7-380

7-381

7-382

7-383

7-384

7-385

7-386

7-387

7-388

7-389

7-390

7-391

7-392

7-393

7-394

7-395

7-396

7-397

7-398

7-399

7-400

7-401

7-402

7-403

7-404

7-405

7-406

7-407

7-408

7-409

7-410

7-411

7-412

7-413

7-414

7-415

7-416

7-417

7-418

7-419

7-420

7-421

7-422

7-423

7-424

7-425

7-426

7-427

7-428

7-429

7-430

7-431

7-432

7-433

7-434

7-435

7-436

7-437

7-438

7-439

7-440

7-441

7-442

7-443

7-444

7-445

7-446

7-447

7-448

7-449

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

By way of example only, provided are schemes for preparing the exemplarySMSMs.

In some embodiments, a scheme for preparing an SMSM described herein isScheme 1:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 2:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 3:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 4:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 5:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 6:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 7:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 8:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 9:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 10:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 11:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 12:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 13:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 14:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 15:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 16:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 17:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 18:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 19:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 20:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 21:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 22:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 23:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 24:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 25:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 26:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 27:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 28:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 29:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 30:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 31:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 32:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 33:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 34:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 35:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 36

In some embodiments, a scheme for preparing an SMSM described herein isScheme 37:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 38:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 39:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 40:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 41:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 42:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 43:

What is claimed is:
 1. A method of treating or ameliorating Huntington'sdisease in a subject, comprising administering to the subject a compoundof Formula (I) or Formula (II), or a pharmaceutically acceptable salt orpharmaceutically acceptable solvate thereof:

wherein, in Formula (I), X is —NR³—, —O—, or —S— and Z is CR², or X is

and Z is N or CR²; in Formula (II),

is a single bond or a double bond, and X is

and Z is C, or X is

and Z is N or CR²; E is —NR—, —O—, —S—, —S(═O)—, —S(═O)₂—, or—S(═O)(═NR^(E))—; R^(A) is hydrogen, deuterium, F, Cl, —CN, —OR¹,—S(═O)R¹, —S(═O)₂R¹, substituted or unsubstituted C₁-C₄ alkyl,substituted or unsubstituted C₁-C₄ haloalkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₄cycloalkyl, or substituted or unsubstituted C₂-C₃ heterocycloalkyl;R^(E) is hydrogen, substituted or unsubstituted C₁-C₃ alkyl, substitutedor unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₂-C₅heterocycloalkyl, substituted or unsubstituted C₂-C₃ alkenyl, orsubstituted or unsubstituted C₂-C₃ alkynyl; ring Q is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl; W issubstituted or unsubstituted C₁-C₃ alkylene, substituted orunsubstituted C₂-C₃ alkenylene, substituted or unsubstituted C₁-C₂heteroalkylene, substituted or unsubstituted C₃-C₈ cycloalkylene, orsubstituted or unsubstituted C₂-C₇ heterocycloalkylene; R is hydrogen,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstitutedC₁-C₄ fluoroalkyl, substituted or unsubstituted C₁-C₄ heteroalkyl,substituted or unsubstituted C₃-C₆ cycloalkyl, or substituted orunsubstituted C₂-C₅ heterocycloalkyl; each R¹ is independently hydrogen,deuterium, substituted or unsubstituted C₁-C₄ alkyl, —CD₃, substitutedor unsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄heteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted C₂-C₅ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; R² is hydrogen,deuterium, substituted or unsubstituted C₁-C₄ alkyl, —CD₃, orsubstituted or unsubstituted C₁-C₄ haloalkyl; R³ is hydrogen, —CN,substituted or unsubstituted C₁-C₄ alkyl, —CD₃, substituted orunsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄heteroalkyl, or —C₁-C₄ alkylene-OR¹; each R⁴ is independently hydrogen,deuterium, substituted or unsubstituted C₁-C₄ alkyl, —CD₃, substitutedor unsubstituted C₁-C₄ haloalkyl, or substituted or unsubstituted C₁-C₄heteroalkyl; each R¹¹, R¹², R¹³, R¹⁴, R¹⁶, and R¹⁷ is independentlyselected from the group consisting of hydrogen, deuterium, F, —OR¹,substituted or unsubstituted C₁-C₄ alkyl, a substituted or unsubstitutedC₁-C₄ fluoroalkyl, and substituted or unsubstituted C₁-C₄ heteroalkyl;R¹⁵ and R¹⁸ are each independently selected from the group consisting ofhydrogen, deuterium, F, —OR¹, substituted or unsubstituted C₁-C₄ alkyl,a substituted or unsubstituted C₁-C₄ fluoroalkyl, and substituted orunsubstituted C₁-C₄ heteroalkyl; a is 0 or 1; b is 0; c is 1; and d is 0or
 1. 2. The method of claim 1, wherein the compound of Formula (I) hasthe structure of Formula (If):


3. The method of claim 1, wherein ring Q is 2-hydroxy-phenyl substitutedwith substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.
 4. The method of claim 3, wherein ring Q is 2-hydroxy-phenylsubstituted with substituted or unsubstituted heteroaryl, wherein ifheteroaryl is substituted then it is substituted with 1 or 2substituents independently selected from: deuterium, halogen, —OH, —NO₂,—CN, —S(═O)R¹, —S(═O)₂R¹, —N(R¹)₂, C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹,—C(═O)N(R¹)₂, substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstitutedC₃-C₇ cycloalkyl, and substituted or unsubstituted C₂-C₇heterocycloalkyl; wherein each R¹ is independently hydrogen, deuterium,substituted or unsubstituted C₁-C₄ alkyl, —CD₃, substituted orunsubstituted C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄heteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted C₂-C₅ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.
 5. The method of claim1, wherein: ring Q is

wherein each R^(Q) is independently selected from hydrogen, deuterium,—F, —Cl, —CN, OH, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, CF₃, OCH₃,—OCH₂CH₃, —CH₂OCH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂; and ring P issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.
 6. The method of claim 5, wherein ring P is substituted orunsubstituted heteroaryl.
 7. The method of claim 6, wherein ring P isheteroaryl selected from the group consisting of:

wherein, each R^(B) is independently selected from hydrogen, deuterium,halogen, hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; R^(B1) is selectedfrom hydrogen, deuterium, substituted or unsubstituted C₁-C₆ alkyl,—CD₃, substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃₋₇cycloalkyl, and substituted or unsubstituted C₂-C₇ heterocycloalkyl; andm is 2 or
 3. 8. The method of claim 1, wherein ring Q is substituted orunsubstituted heteroaryl; wherein if heteroaryl is substituted, then itis substituted with one or more substituents each independently selectedfrom D, halogen, —CN, —NH₂, —OH, ═O, —NH(CH₃), —N(CH₃)₂,—NH(cyclopropyl), —CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃.
 9. The methodof claim 1, wherein ring Q is selected from the group consisting of:

wherein ring Q is optionally substituted with 1, 2, 3, 4, or 5 R^(B),wherein each R^(B) is independently selected from deuterium, halogen,hydroxy, cyano, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ fluoroalkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₁-C₆ alkoxy, deuterium substituted C₁-C₆alkoxy, —OCD₃, substituted or unsubstituted C₃₋₇ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl.
 10. The method ofclaim 1, wherein ring Q is selected from the group consisting of:

R^(B1) is selected from hydrogen, deuterium, substituted orunsubstituted C₁-C₆ alkyl, —CD₃, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₃₋₇ cycloalkyl, and substituted or unsubstituted C₂-C₇heterocycloalkyl.
 11. The method of claim 1, wherein W is substituted orunsubstituted C₁-C₃ alkylene or substituted or unsubstituted C₁-C₂heteroalkylene.
 12. The method of claim 11, wherein W is —CH₂CH₂— or—CH₂CH₂CH₂—.
 13. The method of claim 11, wherein W is —CH₂OCH₂—.
 14. Themethod of claim 1, wherein R is hydrogen, substituted or unsubstitutedC₁-C₄ alkyl, substituted or unsubstituted C₁-C₄ fluoroalkyl, substitutedor unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₅cycloalkyl, or substituted or unsubstituted C₂-C₄ heterocycloalkyl. 15.The method of claim 1, wherein R, R², and R^(A) are hydrogen.
 16. Themethod of claim 1, wherein R¹⁶ is F and R¹⁷ is hydrogen; or wherein R¹⁶is hydrogen and R¹⁷ is F.
 17. The method of claim 1, wherein X is —NR³—and R³ is hydrogen, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂F, —CHF₂, or —CF₃; orwherein X is —NR³— and R³ is hydrogen or —CH₃.
 18. The method of claim1, wherein R¹⁵ and R¹⁸ are both hydrogen or —CH₃.
 19. The method ofclaim 1, wherein R¹⁵ is hydrogen and R¹⁸ is —CH₃; or wherein R¹⁵ is —CH₃and R¹⁸ is hydrogen.
 20. The method of claim 1, wherein at least one ofR¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is or comprises a fluorine.